Next Article in Journal
New Insights into the Pivotal Role of the Amygdala in Inflammation-Related Depression and Anxiety Disorder
Next Article in Special Issue
Hematopoietic and Chronic Myeloid Leukemia Stem Cells: Multi-Stability versus Lineage Restriction
Previous Article in Journal
MDM2-Based Proteolysis-Targeting Chimeras (PROTACs): An Innovative Drug Strategy for Cancer Treatment
Previous Article in Special Issue
Childhood B-Cell Preleukemia Mouse Modeling
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

NSD2 as a Promising Target in Hematological Disorders

Immune System Development and Function Unit, Centro de Biología Molecular Severo Ochoa (CSIC–Universidad Autónoma de Madrid), 28049 Madrid, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(19), 11075; https://doi.org/10.3390/ijms231911075
Submission received: 26 August 2022 / Revised: 15 September 2022 / Accepted: 17 September 2022 / Published: 21 September 2022
(This article belongs to the Special Issue Stem Cell Biology and Cancer)

Abstract

:
Alterations of the epigenetic machinery are critically involved in cancer development and maintenance; therefore, the proteins in charge of the generation of epigenetic modifications are being actively studied as potential targets for anticancer therapies. A very important and widespread epigenetic mark is the dimethylation of Histone 3 in Lysine 36 (H3K36me2). Until recently, it was considered as merely an intermediate towards the generation of the trimethylated form, but recent data support a more specific role in many aspects of genome regulation. H3K36 dimethylation is mainly carried out by proteins of the Nuclear SET Domain (NSD) family, among which NSD2 is one of the most relevant members with a key role in normal hematopoietic development. Consequently, NSD2 is frequently altered in several types of tumors—especially in hematological malignancies. Herein, we discuss the role of NSD2 in these pathological processes, and we review the most recent findings in the development of new compounds aimed against the oncogenic forms of this novel anticancer candidate.

1. Introduction

From a molecular point of view, the term “epigenetics” refers to the mechanisms that regulate the generation, maintenance, and transmission of gene expression and repression patterns without modifying the DNA sequence; this is achieved by the enzymatic addition of specific chemical residues to the different components of chromatin [1,2,3,4,5,6]. These epigenetic modifications ensure that each gene is expressed (or not) at the right time in the correct cellular context; therefore, since they determine which genes are active at any given time, epigenetic marks are in charge of establishing both cell identity and cell function during development. At the chromatin level, epigenetic control is based on an array of chemical modifications of DNA and histones (methylation, phosphorylation, etc.) that can be either added (“written”) or removed (“erased”) by various epigenetic modifier proteins, and can afterwards be “read” by different effector proteins [7,8]. The combination of these marks gives rise to a code (frequently called the ‘‘histone code’’) that specifies the levels of expression or repression of the different genes at the different cellular stages of development. The most important molecular epigenetic regulators are DNA methylation, chromatin remodelers, non-coding RNAs, and, the focus of this review, histone modifications.
The different types of histones can experience many kinds of post-translational modifications (acetylation, phosphorylation, methylation, ubiquitination, SUMOylation, etc.) affecting different amino acid residues along the histone polypeptide chain (Lys, Ser, Thr, Arg), to different degrees (for example, mono-, di-, or trimethylation). In the opposite way, these marks can also be removed by the reciprocal enzymes (demethylases, deacetylases, etc.), therefore altering the interpretation of the code. Interactions between different epigenetic modifications within the same histone molecule or among different ones, and with other marks (DNA methylation, etc.) determine the final functional outcome regarding DNA accessibility and transcription.
Methylation is one of the most important and best characterized histone modifications. Additionally, it is one of the more versatile; for instance, the methylation of histone H3 at lysines 4, 36, or 79 (H3K4, H3K36, and H3K79) is mainly linked to active gene transcription, whereas the methylation of histone H3 at lysines 9 or 27 (H3K9, H3K27), and histone H4 at lysine 20 (H4K20), is usually associated with gene repression [9,10]. In this way, we can also see that some modifications are antagonistic in their effects, and therefore, they are usually mutually exclusive. Methylation of lysines on histones, and in other proteins, is catalyzed by protein lysine methyltransferases (KMTs), and the methyl group can be removed by protein lysine demethylases (KDMs). In the human genome, over 100 KMTs have been predicted, and mass spectrometry studies have suggested that more than 1000 different proteins can be methylated in lysine residues [11,12,13]. In this review, we will mainly focus on a specific modification, which is the methylation of Lysine 36 of Histone 3 (H3K36), and on the physiological and pathological roles of the main enzyme responsible for its dimethylation (H3K36me2), NSD2 (also known as MMSET—Multiple Myeloma SET domain—or WHSC1 –Wolf–Hirschhorn Syndrome Candidate 1–). The methylation of H3K36 exists in three different statuses: mono- (H3K36me), di- (H3K36me2), and trimethylated (H3K36me3); the second one being the most abundant form. H3K36me3 is closely associated with the gene bodies of active genes [14,15], while the H3K36me2 mark is mostly found in intergenic regions and promoters in different cell types, such as sarcoma or myeloma cells [16,17]. H3K36 dimethylation in vivo is mainly catalyzed by four different, but related, KMTS (NSD1, NSD2, NSD3, and ASH1L) (see below) [18], whereas there is only one enzyme capable of synthesizing H3K36me3 in vivo, and that is SETD2. The protein capable of catalyzing H3K36me1 generation is still unknown, although it is probable that it is generated through the combined actions of KMTs and KDMs. The known H3K36 histone demethylases, which oppose the action of the methyltransferases, belong to the Jumonji C (JmjC) domain-containing family of histone demethylases (JHDMs) [19]. Specifically, there are two JHDMs capable of demethylating H3K36: JHDM1 (also known as KDM2A-B), which acts on H3K36me1 and H3K36me2, and JHDM3 (JMJD2/KDM4A-D), which demethylates H3K36me2 and H3K36me3 [20]. As we will see, H3K36 methylation is involved in several crucial biological processes including chromatin organization [21], transcripts processing and alternative splicing [22,23,24], and DNA damage repair [25,26].

2. Deregulation of H3K6methylation and Cancer

The degree of methylation of H3K36 results in different biological consequences, and mutations in the enzymes controlling this mark can result in diverse developmental disorders, and cancer [11]. SETD2 (generating H3K36me3) has been shown to regulate DNA methylation, transcription, RNA processing, RNA epigenetics marks-like N6-Methyladenosine (m6A), and DNA repair [27,28,29,30,31]. How this deregulation of SETD2 gives rise to cancer in many different tissues has already been extensively documented elsewhere [11,32,33,34,35,36,37,38]. In contrast to these outcomes caused by the alterations in the H3K36me3 deposition, the molecular consequences of H3K36 dimethylation are less understood; until recently, it was simply considered a step towards trimethylation, but it is now clear that it has specific roles in itself, and it has been linked to DNA methylation, gene activation, or cellular transformation, for example [16,39,40]. In contrast to the well-established role of SETD2 as a tumor suppressor, the enzymes involved in generating the H3K36me2 mark are primarily active oncogenes upon activating mutations/translocations and, conversely, are mainly associated with developmental problems when completely or partially inactivated [18].
The disruption of epigenetic mechanisms can lead to altered gene function and malignant cellular transformation. In fact, the alterations of the epigenetic landscape constitute a hallmark of cancer [41]. Given the relevant role of the H3K36me2/3 marks in different biological processes, their alteration can be involved in the initiation or maintenance of different types of malignancies [42,43]. For instance, an enrichment of H3K36me3 in oncogenes is tightly related to the aberrant overexpression of these genes in cancer cells [44]. Here, we will focus on the normal and pathological functions of NSD2, which is involved in the initiation and relapse of a wide range of cancers. The altered expression of NSD2 can affect global histone methylation enrichment and high order chromatin organization, leading to the development of diseases such as multiple myeloma or lung cancer [45,46,47]. In myeloma cells, H3K36 methylation is globally increased (in fact, NSD2 was first identified as MMSET—Multiple Myeloma SET domain protein—in human disease [48]), and consequently, its opposed mark, H3K27me3, decreases, leading to the aberrant activation of genes related to cellular adhesion, cell proliferation, and carcinogenesis [47,49,50,51]. In lung cancer patients, NSD2 overexpression and uncontrolled H3K36me2 enrichment lead to rapid tumor progression and also to a poorer outcome, and NSD2 inhibition disrupts the activation of RAS-target genes, contributing to the inhibition of the RAS-mediated oncogenic transcriptional programs [45,52].
Altered H3K36 methylation also impairs the proper differentiation of mesenchymal progenitor cells, leading to sarcomagenesis [53]. NSD2 is also highly expressed in metastatic prostate cancer, where its repression can inhibit metastasis [54], so that NSD2 has been proposed as a key driver of the tumor, and therefore, as a critical therapeutic target for this disease.

3. NSD2 Protein: General Features

The members of the NSD (Nuclear SET Domain) protein family are structurally conserved methyltransferases [18,40]; the family is formed by NSD1, NSD2, and NSD3 (also known as WHSC1L1—Wolf–Hirschhorn Syndrome Candidate 1-Like 1–) (Figure 1). They present several isoforms that significantly vary in length; the longest isoforms are large proteins containing many defined domains, amongst which the most relevant one is the methyltransferase catalytic domain SET (Su(var)3-9, Enhancer-of-zeste, Trithorax), which can be further subdivided into pre-SET, SET, and post-SET domains [55,56]. The SET domain catalyzes the transfer of the methyl group from S-adenosylmethionine (SAM) to the substrate protein, and propagates the H3K36me2 active mark to nearby nucleosomes; apparently, it is also capable of trimethylating H3K36 in the presence of SETDB1 [57,58]. Additionally, full-length isoforms have, in the amino-terminal portion, a high-mobility-group (HMG) box, two PWWP domains necessary for binding to methylated Histone 3, as well as the DNA and PHD (plant-homeodomain) domains necessary for the interactions with other modified histones [59,60,61] (Figure 1). These multiple protein–protein interaction (PPI) modules can act as potential chromatin readers, and the evidence indicates that they play important roles in NSD protein function, although their precise functions are still being elucidated [62]. PWWP domains are known to possess the capacity of reading the presence of H3K36-me2 or -me3 marks while, at the same time, binding the nucleosomal DNA besides the H3K36 residue [63,64]. The most N-terminal domain of NSD2 can bind to nucleosomes di- and tri-methylated in H3K36, supposedly stabilizing NSD2 binding to chromatin [61].
NSD1 and NSD2 are crucial for proper murine embryonic development, since their knockouts are embryonic lethal [65,66], and NSD3 is critical for correct neural crest development [67,68]. In humans, congenital heterozygous mutations of NSD1 cause Sotos syndrome, a severe developmental defect occurring in 1/14,000 births and causing excessive growth, advanced bone age, a characteristic face, neurological disorders, brain abnormalities, and intellectual disability [69]. Similarly, a hemizygous chromosomal deletion affecting NSD2 causes Wolf–Hirschhorn syndrome (WHS), characterized by growth deficiency, immunodeficiencies, a characteristic facial appearance, intellectual disability, and seizures [70,71,72].
NSD proteins can methylate in vitro many different histone residues: H3K4, H3K9 H3K27, H3K36, H3K79, and H4K20; however, in vivo, their function is largely restricted to the mono- and di-methylation of H3K36, and to a much lesser degree, H4K20 [47,73,74]. One important structural particularity of the NSD proteins, which present a major challenge for the development of specific inhibitors [75], is the presence of an autoinhibitory loop, which connects the SET and post-SET domains and blocks the catalytic domain in the substrate-unbound enzyme [76,77], in such a way that it is only accessible after a conformational change triggered by the binding to the nucleosomal DNA [11,73]. Therefore, the development of inhibitors will very likely require screening designs performed in the presence of assembled nucleosomes.

4. NSD2 Mutations and Their Oncogenic Consequences

NSD2 is one of the most frequently mutated epigenetic regulators in several cancer types, especially pediatric cancers [78]. Different types of mutations have been described in NSD2, which are associated with several human pathologies. As mentioned, an insufficiency of NSD2 is established as one of the main causes of Wolf–Hirschhorn syndrome, and its associated defects in B cell development and immune function [70,71,72,79]. On the contrary, NSD2 hyper-activation caused by either point mutations or genomic translocations represents a relevant cause of B-cell-associated hematological malignancies, such as multiple myeloma and acute leukemia, and other types of cancers including colon cancer and lung carcinoma [45,78,80,81,82].
Focusing on the NSD2 mutations found in hematopoietic pathologies and malignancies (Figure 2), these could be classified into:

4.1. Gain-of-Function Mutations

4.1.1. Acute Lymphoblastic Leukemia

B-cell acute lymphoblastic leukemia (B-ALL) is a clonal malignant disease that originates in a single cell and is characterized by an accumulation of immature B-cells that are phenotypically reminiscent of the normal stages of B-cell differentiation. This alteration finally leads to the suppression of normal hematopoiesis and the infiltration of many vital organs [83]. Relapsed B-cell Acute Lymphoblastic Leukemia (B-ALL) remains a leading cause of cancer mortality in children [83,84], accounting for 15–20% of the pediatric cases. Intriguingly, the mutations of epigenetic modifiers are found in a great amount of patients at relapse, suggesting a role for the epigenome in disease progression and therapy resistance [78,84,85,86]. NSD2 stands out as one of the genes mutated in a relapse-specific manner, with different mutations in the catalytic SET domain, among which p.Glu1099Lys (E1099K) is the most recurrent, leading to leukemic cell proliferation [80]. NSD2 mutated subclones at early stages of the disease results into “first settler” clones at relapse [86]. This NSD2E1099K mutation is enriched in a B-cell leukemia subgroup characterized by the presence of the fusion gene ETV6-RUNX1 as a primary oncogenic lesion [80].
Point mutations taking place in E1099K, D1125N, and T1150A NSD2 positions enhance the interaction with chromatin nucleosomes, producing enzyme hyperactivity [80,87,88,89,90,91,92,93,94,95,96,97,98,99]. Specifically, E1099K and T1150A mutations destabilize the auto-inhibitory loop located in the catalytic site of the enzyme, keeping it in an open state and therefore promoting the enhancement of its catalytic activity [88]. Compared to control cells, those cells carrying the E1099K mutation present increased H3K36me2 enrichment, with a parallel decrease in the antagonistic mark H3K27me3; this causes a 3D genome reorganization that maintains the open chromatin state compartments and leads to higher proliferation rates [87,90]. Thus, alterations in this epigenetic regulator trigger epigenetic changes, higher order chromatin reorganization, changes in genes expression, and finally, phenotypical consequences such as aberrant cell proliferation capacity.
All these molecular mechanisms by which NSD2 confers treatment resistance represent an essential stage for disease relapse and are still under study. The global chromatin reorganization suffered by ALL cells due to NSD2 hyper-activation points towards epigenetic landscape modification as one of the main regulators of cellular fitness and response to the environment [84]. More recent studies using high-throughput drug screenings have unveiled that uncontrolled NSD2 activity caused by E1099K mutation is related to glucocorticoids resistance [91]. The uncontrolled cell growth and clone enrichment at relapse reinforce the potential role of NDS2 as an oncogene, and as a potential target for the development of specific inhibitors for efficient leukemia treatment.

4.1.2. Multiple Myeloma

Multiple myeloma (MM) is a hematological malignancy characterized by the abnormal accumulation of clonal plasma cells in the bone marrow [92]. MM accounts for 10% of hematological malignancies and 1.6% of all U.S. cancer deaths. The median age at diagnosis is 69 years. Genetic aberrations are observed from the early stages of the disease and are key events in the establishment of the clonal plasma cell population. MM can be classified into two major subtypes: hyperdiploid and non-hyperdiploid. The second type is mainly characterized by translocations leading to the activation of proto-oncogenes located in multiple partner chromosomes. Approximately 15–20% of MM patients carry a translocation in the chromosome 4 (t(4;14)) that puts NSD2 expression under the control of the immunoglobulin heavy chain locus, leading to its overexpression, and a consequent global increase in H3K36me2, coupled with a global H3K27me3 decrease through EZH2 inhibition [16,17,48]. In fact, the disorganization in H3K36me2 distribution is one of the first steps of the myeloma oncogenic program, due to the alteration in gene expression patterns involved in cell growth, adhesion, chromatin accessibility, and DNA damage response [16,47,49,51,93]. Additionally, the DNA damage repair capacity of cells overexpressing NSD2 could explain their resistance to treatment [94]. C-MYC stands out among the genes with altered expression levels upon NSD2 overexpression, attributed to miR126 aberrant repression [95]. In fact, TP53 and C-MYC have been postulated as key targets of NSD2 in MM, and their altered expressions are directly related with aggressiveness and a poorer outcome in different subsets of myeloma patients (including both NSD2-related myeloma patients and NSD2 non-related ones) [96,97].
However, NSD2 enzymatic activity is not only altered upon chromosome translocation in myeloma patients. There is increasing evidence of myeloma patients that harbor the aforementioned E1099K point mutation, which is not exclusive to ALL patients; also in MM, this mutation leads to NSD2 hyper activation with H3K36me2 global enhancement, H2k27me3 global decrease, and a consequent alteration of the gene expression patterns [81].
Given that NSD2 is known to play a relevant role in multiple myeloma relapse and treatment resistance [94,98], genetic and epigenetic compounds should be found capable of inhibiting NSD2 activity regardless of the nature of its alteration.

4.1.3. Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is an uncommon incurable and aggressive B-cell lymphoma; it is a heterogeneous disease with variable presentations, and nowadays, it is in fact considered a mixed bag of several subtypes of non-Hodgkin’s lymphomas with a spectrum of molecular and clinical features. NSD2 is one of the most commonly mutated genes in mantle cell lymphoma, and it is associated with poor prognosis [99,100,101]. Interestingly, both E1099K and T1150A mutations are also found in mantle cell lymphoma, associating the disease with the hyperactivity of the enzyme. In fact, the alterations of NSD2 function can be triggered from either E1099K mutation, the T1150A mutation or a combination of both, again leading to the overexpression of genes related to proliferation and cell cycle regulation [87,102]. The T1150A mutation produces the formation of additional hydrogen bonds, which facilitate the insertion of the histone into the catalytic pocket of the enzyme [103].

4.1.4. Acute Myeloid Leukemia (AML)

Several cases of human acute leukemia, including both AML and ALL, were linked to SETD2 mutation events, normally associated with additional chromosomal abnormalities [34]. Furthermore, recent studies postulated that AML patients carrying mutations in SETD2 are more resistant to treatment due to the defects in cell cycle checkpoints [104]. Given that SETD2 and NSD2 present a similar catalytic domain, it would be reasonable to hypothesize that mutations in NSD2 could be associated with AML development.
No evidence has been published to date, and preliminary results do not assign poorer outcomes to AML patients from different cohorts stratified according to NSD1 and NSD2 expression levels [105]. However, alterations in NSD1 and NSD2 function have been linked to erythroleukemia development, a subtype of acute myeloid leukemia; indeed, it has been reported that NSD1 is a critical regulator of erythroid differentiation, since its knockdown impaired proper erythroblast maturation and induced erythroleukemia in mice [106]. NSD2 has also been described as a master regulator of erythroid differentiation [107]. In this case, NSD2 expression is inversely correlated to BRCA1 activity and erythroid differentiation in leukemia cell lines. The degradation and loss of NSD2 stability promoted by BRCA1, induces hemin-dependent leukemia cell differentiation [107]. Thus, the interaction between NSD2 and BRCA1 could become a target mechanism to establish new therapies for erythroleukemia.

4.1.5. Other Hematopoietic Malignancies

In general, the main hematopoietic tumors in which NSD2 mutations seem to play a significant role in cancer development or evolution are those described in the previous sections. In fact, in a screening of 181 “Cancer Cell Line Encyclopedia” cell lines of hematopoietic origin including chronic myeloid leukemia (), Burkitt’s lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and Hodgkin’s lymphoma HL (HL) samples, among other hematopoietic cancer types, only six B-ALL cell lines and one myeloma cell line were found to harbor the E1099K alteration, plus eight myeloma cell lines that contained the t(4;14) translocation [80]. A larger screening of patient’s samples, part of the American Association for Cancer Research “GENIE” initiative [108], has recently identified occasional mutations of NSD2 in small percentages of hematologic cancers such as non-Hodgkin lymphomas (NSD2 is altered in 2.86% of the patients), Hodgkin lymphoma (1.79%), diffuse large B-cell lymphoma (2.58%), or chronic lymphocytic leukemia/small lymphocytic lymphoma (0.53%) [108]. These small percentages are in reasonable agreement with those found in the COSMIC database [109] and seem to suggest that, although NSD2 mutations can be involved in the tumor progression in many different types of hematopoietic malignancies, its most relevant pathological role is played in the context of B-ALL, MM, and MCL.

4.2. Loss-of-Function Mutations

As previously mentioned, the hemizygous loss of NSD2 is related par excellence to the Wolf–Hirschhorn Syndrome (WHS), where a variable segment of chromosome 4 is lost, including the WHSC1-containing region [65,70]; WHS is a rare disease, with a prevalence of 1:20,000/50,000 worldwide, which affects the whole organism causing severe developmental defects, including failures in antibody production and other lymphocyte functions [110].
Patients with developmental disorders other than WHS can also carry NSD2 loss-of-function mutations, such as S1137F or Y1179A, which impair the enzyme catalytic activity and consequently, diminish H3K36 dimethylation levels [111,112]. The fact that the symptoms from patients carrying these mutations do not completely overlap with those of WHS patients suggests that the molecular consequences of H3K36me2 loss caused either by NSD2 deletion or by loss-of-function mutations present some differences that will need further research [111,112].
Regarding the implications of NSD2 loss-of-function in cancer, it has been reported that it can also have tumor suppressor functions controlling progenitor cell differentiation. It has been reported that, upon NSD2 knockout, zebrafish presented developmental defects resembling Wolf–Hirschhorn Syndrome; however, at later stages, these animals developed swim bladder tumors, indicating a potential tumor suppressor function of NSD2 [113].

5. NSD2 Inhibitors and Therapeutic Strategies

Many histone lysine methyl-transferases have been highlighted as promising therapeutic targets in cancer, and members of the NSD family are not an exception. As previously explained, their activating mutations and up-regulation seem to drive both tumor progression and treatment resistance in several types of cancer. Accordingly, extensive research has been conducted in recent years in order to identify the different selective inhibitors to target the catalytic domain of NSD proteins [87] (Table 1).
Given that NDS proteins contain a catalytic SET domain shared with other proteins included in the same super family of histone methyltransferases, some NSD inhibitors were initially reported as inhibitors for other SET domain-containing enzymes; for example, BIX-01294 was initially identified as a G9a-like protein (GLP) inhibitor, capable of reducing H3K9me2 levels during induced cell reprogramming [114,115]. BIX-01294 binds to the enzymatic SET domain of GLP and similarly, to the SET domain of NSD, obtaining in fact a better inhibition rate on NSD2 protein [116]. This finding contributed to the study of NSD proteins biology and to the development of selective NSD inhibitors, but more extensive research is required to increase target specificity.
Sinefungin, a natural nucleoside isolated from Streptomyces and related to S-adenosylmethionine, has been widely postulated as a nonselective inhibitor of the SET domain activity; it was first tested on SETD2 [117], and then the potential of sinefungin analogues for NSD2 inhibition was also tested. Despite the fact that these proteins present slight differences in their substrate binding pockets and their SET domains’ 3D organization, the findings provided a helpful contribution for further research on the selective inhibitors of NSD2 protein [118]. Along the same lines, given the similarity in function and structural conservation among the different H3K36me2 methyltransferases, it would be reasonable to apply the therapeutic agents designed against one enzyme to the others, thereby reducing the development of new inhibitors for the same kind of targets. For example, one could use the recently developed ASHL1 inhibitors in cases of NSD2 hyperactivation [119]. However, even though NSD2 and ASHL1 both present the autoinhibitory loop in the SET domain, which would be necessary for this type of inhibition, the sequence of this loop is poorly conserved among proteins and restricts the inhibition effectivity to only AHSL1 [119,120].
The first validated peptide specific inhibitor against the catalytic activity of NSD2 in multiple myeloma cases was PTD2 [121], whose inhibitor effect is specific in the presence of the cofactor S-adenosyl-L-methionine (SAM). After multiple assays, a useful pipeline for the discovery of selective NSD2 inhibitors by the high-throughput screening of small molecules was developed, which led to the description of five potential inhibitors for NSD2 activity: DA-3003-1, PF-03882845, chaetocin, TC LPA5 4, and ABT-199. All compounds exhibited similar effectivity on either WT or mutated (E1099K and T1150A) NSD2 enzyme forms [122].
Recently, the, Di Luccio laboratory has discovered LEM-06 and LEM-14, which seem to be NSD2-specific inhibitors (with weak activity on NSD1 and NSD3 proteins) [123,124]. They put forward LEM-14 and LEM-14-1189 as promising tools for investigating the biology of the NSDs, and they represent a relevant step in the further development of specific NSD inhibitors used to treat malignancies, including multiple myeloma [124].
Using high-throughput compound screenings, 5-Aminonaphthalene derivatives have emerged very recently as selective inhibitors of NSD2 activity in multiple myeloma and acute lymphoid leukemia cell lines. Cells exhibit increased apoptosis and cell death rates upon the action of these inhibitors, among which compound 9c stands out, which inhibits NSD2 catalytic activity, and consequently, so does the transcriptional activity of NSD2 target genes [125].
Since the structure of NSD proteins contains many domains (in addition to the catalytic SET domain itself) that play an important role in protein activity, other approaches are being developed to target methyltransferase activity by interfering with those domains. It has recently been found that the PWWP domains can be themselves druggable, and a chemical probe targeting NSD3 N-terminal PWWP domain can reduce the proliferation of leukemic cell lines [126]. Additionally, an antagonist of the equivalent PWWP domain in NSD2 can abrogate the binding to H3K36me2 [127], therefore proving that targeting other domains beyond the SET could lead to the efficient modulation of NSD2 binding to chromatin and, therefore, its subcellular localization, and perhaps even its catalytic function [62]. Recently, the use of virtual and target class screenings has allowed the identification of a first-in-class chemical probe, UNC6934, that selectively binds an aromatic cage in NSD2-PWWP1, leading to the disruption of its interaction with H3K36me2 nucleosomes [62,127]. UNC6934 can bind full-length NSD2 in a specific and potent manner, and can trigger its dissociation from chromatin, therefore disrupting a cooperative chromatin binding and the methylation mechanism, which seems to require the concerted action of multiple protein domains.
Finally, more indirect approaches are also possible; for example, inhibitors of the epigenetic repressor complex PRC2 were postulated as promising therapeutic agents against relapsed NSD2-mutated B-ALL cells [91]. The alteration of global histone methylation pattern caused by NSD2 hyperactivation affected the expression of the glucocorticoid receptor (GR), therefore inhibiting the cellular response to glucocorticoid (GC) treatment. Upon PRC2 inhibitor treatment, there was an increase in the number of GRs, hence restoring the response to GC treatment, and activating the expression of pro-apoptotic genes in B-ALL cells.

6. Conclusions and Future Perspectives

Somatic mutations were identified in the majority of genes coding for histone methyl transferases in many types of cancers, most of which are resistant to treatment, therefore reinforcing the idea of the influence of the epigenetic and global chromatin landscape in tumor development and relapse.
This review highlights the role of the epigenetic regulator NSD2 in different hematological malignancies. NSD2 was established as a promising target for the treatment of several types of hematological cancers, since both enhanced expression and increased activity caused by either chromosome translocations or different point mutations are involved in tumor progression and treatment resistance. Mutations and deletions disrupting NSD2 function were also linked to disease, but most of the patients present a clinical profile related to developmental disorders, rather than malignant tumors.
In recent years, great efforts have been made to identify the different mutations that affect NSD2 catalytic activity, as well as to develop the selective inhibitors of such activity. Valuable contributions to the discovery and optimization of potent and specific inhibitors of NSD2 have been made in hematological malignancies, especially in acute leukemia, which have greatly contributed to understanding the role of these enzymes in both normal and pathologic development in different types of hematopoietic cells. The most recent research publications are shedding new light on the NSD2-related mechanisms involved in relapse and resistance to treatment, such as the loss of response to glucocorticoids [92]. These findings represent an essential step in the field, but further basic and clinical studies are needed to fully understand the regulation of the H3K36 mark in development and disease, and to refine therapeutic strategies for relapsed cancers.

Funding

Research at C.C.’s laboratory was partially supported by the Ministerio de Ciencia e Innovación/AEI/FEDER (PID2021-122787OB-I00), by the Fundación Científica de la Asociación Española contra el Cáncer (PRYCO211305SANC), and by a Research Contract with the Fundación Síndrome de Wolf–Hirschhorn o 4p-. Institutional grants from the Fundación Ramón Areces and Banco de Santander to the CBMSO are also acknowledged. The C.C. laboratory was member of the EU COST Action LEGEND (CA16223).

Acknowledgments

The authors thank all the scientists who contributed to the field reviewed in this manuscript and apologize to those colleagues they were unable to cite due to space restrictions.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Pirrotta, V. The Necessity of Chromatin: A View in Perspective. Cold Spring Harb. Perspect. Biol. 2016, 8, a019547. [Google Scholar] [CrossRef] [PubMed]
  2. Seto, E.; Yoshida, M. Erasers of histone acetylation: The histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol. 2014, 6, a018713. [Google Scholar] [CrossRef] [PubMed]
  3. Cheng, X. Structural and functional coordination of DNA and histone methylation. Cold Spring Harb. Perspect. Biol. 2014, 6, a018747. [Google Scholar] [CrossRef] [PubMed]
  4. Zoghbi, H.Y.; Beaudet, A.L. Epigenetics and Human Disease. Cold Spring Harb. Perspect. Biol. 2016, 8, a019497. [Google Scholar] [CrossRef]
  5. Patel, D.J. A Structural Perspective on Readout of Epigenetic Histone and DNA Methylation Marks. Cold Spring Harb. Perspect. Biol. 2016, 8, a018754. [Google Scholar] [CrossRef]
  6. Almouzni, G.; Cedar, H. Maintenance of Epigenetic Information. Cold Spring Harb. Perspect. Biol. 2016, 8, a019372. [Google Scholar] [CrossRef]
  7. Allis, C.D.; Jenuwein, T. The molecular hallmarks of epigenetic control. Nat. Rev. Genet. 2016, 17, 487–500. [Google Scholar] [CrossRef]
  8. Zhao, Y.; Garcia, B.A. Comprehensive Catalog of Currently Documented Histone Modifications. Cold Spring Harb. Perspect. Biol. 2015, 7, a025064. [Google Scholar] [CrossRef]
  9. Greer, E.L.; Shi, Y. Histone methylation: A dynamic mark in health, disease and inheritance. Nat. Rev. Genet. 2012, 13, 343–357. [Google Scholar] [CrossRef]
  10. Kouzarides, T. Chromatin modifications and their function. Cell 2007, 128, 693–705. [Google Scholar] [CrossRef] [Green Version]
  11. Husmann, D.; Gozani, O. Histone lysine methyltransferases in biology and disease. Nat. Struct. Mol. Biol. 2019, 26, 880–889. [Google Scholar] [CrossRef]
  12. Carlson, S.M.; Gozani, O. Nonhistone Lysine Methylation in the Regulation of Cancer Pathways. Cold Spring Harb. Perspect. Med. 2016, 6, a026435. [Google Scholar] [CrossRef]
  13. Clarke, S.G. Protein methylation at the surface and buried deep: Thinking outside the histone box. Trends Biochem. Sci. 2013, 38, 243–252. [Google Scholar] [CrossRef]
  14. Mikkelsen, T.S.; Ku, M.; Jaffe, D.B.; Issac, B.; Lieberman, E.; Giannoukos, G.; Alvarez, P.; Brockman, W.; Kim, T.K.; Koche, R.P.; et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 2007, 448, 553–560. [Google Scholar] [CrossRef]
  15. Zemach, A.; McDaniel, I.E.; Silva, P.; Zilberman, D. Genome-wide evolutionary analysis of eukaryotic DNA methylation. Science 2010, 328, 916–919. [Google Scholar] [CrossRef]
  16. Kuo, A.J.; Cheung, P.; Chen, K.; Zee, B.M.; Kioi, M.; Lauring, J.; Xi, Y.; Park, B.H.; Shi, X.; Garcia, B.A.; et al. NSD2 links dimethylation of histone H3 at lysine 36 to oncogenic programming. Mol. Cell 2011, 44, 609–620. [Google Scholar] [CrossRef]
  17. Popovic, R.; Martinez-Garcia, E.; Giannopoulou, E.G.; Zhang, Q.; Zhang, Q.; Ezponda, T.; Shah, M.Y.; Zheng, Y.; Will, C.M.; Small, E.C.; et al. Histone Methyltransferase MMSET/NSD2 Alters EZH2 Binding and Reprograms the Myeloma Epigenome through Global and Focal Changes in H3K36 and H3K27 Methylation. PLoS Genet. 2014, 10, e1004566. [Google Scholar] [CrossRef]
  18. Wagner, E.J.; Carpenter, P.B. Understanding the language of Lys36 methylation at histone H3. Nat. Rev. Mol. Cell Biol. 2012, 13, 115–126. [Google Scholar] [CrossRef]
  19. Tsukada, Y.; Fang, J.; Erdjument-Bromage, H.; Warren, M.E.; Borchers, C.H.; Tempst, P.; Zhang, Y. Histone demethylation by a family of JmjC domain-containing proteins. Nature 2006, 439, 811–816. [Google Scholar] [CrossRef]
  20. Hyun, K.; Jeon, J.; Park, K.; Kim, J. Writing, erasing and reading histone lysine methylations. Exp. Mol. Med. 2017, 49, e324. [Google Scholar] [CrossRef] [Green Version]
  21. Lhoumaud, P.; Badri, S.; Rodriguez-Hernaez, J.; Sakellaropoulos, T.; Sethia, G.; Kloetgen, A.; Cornwell, M.I.; Bhattacharyya, S.; Ay, F.; Bonneau, R.; et al. NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains. Nat. Commun. 2019, 10, 4843. [Google Scholar] [CrossRef]
  22. Guo, R.; Zheng, L.; Park, J.W.; Lv, R.; Chen, H.; Jiao, F.; Xu, W.; Mu, S.; Wen, H.; Qiu, J.; et al. BS69/ZMYND11 Reads and Connects Histone H3.3 Lysine 36 Trimethylation Decorated Chromatin to Regulated Pre-mRNA Processing. Mol. Cell 2014, 56, 298. [Google Scholar] [CrossRef]
  23. Leung, C.S.; Douglass, S.M.; Morselli, M.; Obusan, M.B.; Pavlyukov, M.S.; Pellegrini, M.; Johnson, T.L. H3K36 Methylation and the Chromodomain Protein Eaf3 Are Required for Proper Cotranscriptional Spliceosome Assembly. Cell Rep. 2019, 27, 3760–3769.e4. [Google Scholar] [CrossRef]
  24. Mirabella, F.; Murison, A.; Aronson, L.I.; Wardell, C.P.; Thompson, A.J.; Hanrahan, S.J.; Fok, J.H.L.; Pawlyn, C.; Kaiser, M.F.; Walker, B.A.; et al. A Novel Functional Role for MMSET in RNA Processing Based on the Link Between the REIIBP Isoform and Its Interaction with the SMN Complex. PLoS ONE 2014, 9, e99493. [Google Scholar] [CrossRef]
  25. de Krijger, I.; van der Torre, J.; Peuscher, M.H.; Eder, M.; Jacobs, J.J.L. H3K36 dimethylation by MMSET promotes classical non-homologous end-joining at unprotected telomeres. Oncogene 2020, 39, 4814–4827. [Google Scholar] [CrossRef]
  26. Li, F.; Mao, G.; Tong, D.; Huang, J.; Gu, L.; Yang, W.; Li, G.M. The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα. Cell 2013, 153, 590–600. [Google Scholar] [CrossRef]
  27. Edmunds, J.W.; Mahadevan, L.C.; Clayton, A.L. Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. EMBO J. 2008, 27, 406–420. [Google Scholar] [CrossRef]
  28. Jha, D.K.; Pfister, S.X.; Humphrey, T.C.; Strahl, B.D. SET-ting the stage for DNA repair. Nat. Struct. Mol. Biol. 2014, 21, 655–657. [Google Scholar] [CrossRef]
  29. Wen, H.; Li, Y.; Xi, Y.; Jiang, S.; Stratton, S.; Peng, D.; Tanaka, K.; Ren, Y.; Xia, Z.; Wu, J.; et al. ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression. Nature 2014, 508, 263–268. [Google Scholar] [CrossRef]
  30. Baubec, T.; Colombo, D.F.; Wirbelauer, C.; Schmidt, J.; Burger, L.; Krebs, A.R.; Akalin, A.; Schubeler, D. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 2015, 520, 243–247. [Google Scholar] [CrossRef]
  31. Huang, H.; Weng, H.; Zhou, K.; Wu, T.; Zhao, B.S.; Sun, M.; Chen, Z.; Deng, X.; Xiao, G.; Auer, F.; et al. Histone H3 trimethylation at lysine 36 guides m(6)A RNA modification co-transcriptionally. Nature 2019, 567, 414–419. [Google Scholar] [CrossRef] [PubMed]
  32. Duns, G.; van den Berg, E.; van Duivenbode, I.; Osinga, J.; Hollema, H.; Hofstra, R.M.; Kok, K. Histone methyltransferase gene SETD2 is a novel tumor suppressor gene in clear cell renal cell carcinoma. Cancer Res. 2010, 70, 4287–4291. [Google Scholar] [CrossRef] [PubMed]
  33. Dalgliesh, G.L.; Furge, K.; Greenman, C.; Chen, L.; Bignell, G.; Butler, A.; Davies, H.; Edkins, S.; Hardy, C.; Latimer, C.; et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 2010, 463, 360–363. [Google Scholar] [CrossRef] [PubMed]
  34. Zhu, X.; He, F.; Zeng, H.; Ling, S.; Chen, A.; Wang, Y.; Yan, X.; Wei, W.; Pang, Y.; Cheng, H.; et al. Identification of functional cooperative mutations of SETD2 in human acute leukemia. Nat. Genet. 2014, 46, 287–293. [Google Scholar] [CrossRef]
  35. Parker, H.; Rose-Zerilli, M.J.; Larrayoz, M.; Clifford, R.; Edelmann, J.; Blakemore, S.; Gibson, J.; Wang, J.; Ljungstrom, V.; Wojdacz, T.K.; et al. Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia. Leukemia 2016, 30, 2179–2186. [Google Scholar] [CrossRef]
  36. Viaene, A.N.; Santi, M.; Rosenbaum, J.; Li, M.M.; Surrey, L.F.; Nasrallah, M.P. SETD2 mutations in primary central nervous system tumors. Acta Neuropathol. Commun. 2018, 6, 123. [Google Scholar] [CrossRef]
  37. Gui, Y.; Guo, G.; Huang, Y.; Hu, X.; Tang, A.; Gao, S.; Wu, R.; Chen, C.; Li, X.; Zhou, L.; et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat. Genet. 2011, 43, 875–878. [Google Scholar] [CrossRef]
  38. Huang, K.K.; McPherson, J.R.; Tay, S.T.; Das, K.; Tan, I.B.; Ng, C.C.; Chia, N.Y.; Zhang, S.L.; Myint, S.S.; Hu, L.; et al. SETD2 histone modifier loss in aggressive GI stromal tumours. Gut 2016, 65, 1960–1972. [Google Scholar] [CrossRef]
  39. Li, J.; Ahn, J.H.; Wang, G.G. Understanding histone H3 lysine 36 methylation and its deregulation in disease. Cell Mol. Life Sci. 2019, 76, 2899–2916. [Google Scholar] [CrossRef]
  40. Bennett, R.L.; Swaroop, A.; Troche, C.; Licht, J.D. The Role of Nuclear Receptor–Binding SET Domain Family Histone Lysine Methyltransferases in Cancer. Cold Spring Harb. Perspect. Med. 2017, 7, a026708. [Google Scholar] [CrossRef] [Green Version]
  41. Esteller, M. Epigenetics in cancer. N. Engl. J. Med. 2008, 358, 1148–1159. [Google Scholar] [CrossRef]
  42. Xiao, C.; Fan, T.; Tian, H.; Zheng, Y.; Zhou, Z.; Li, S.; Li, C.; He, J. H3K36 trimethylation-mediated biological functions in cancer. Clin. Epigenet. 2021, 13, 199. [Google Scholar] [CrossRef]
  43. Yuan, S.; Natesan, R.; Sanchez-Rivera, F.J.; Li, J.; Bhanu, N.V.; Yamazoe, T.; Lin, J.H.; Merrell, A.J.; Sela, Y.; Thomas, S.K.; et al. Global Regulation of the Histone Mark H3K36me2 Underlies Epithelial Plasticity and Metastatic Progression. Cancer Discov. 2020, 10, 854–871. [Google Scholar] [CrossRef]
  44. Zhang, L.Q.; Li, Q.Z.; Jin, W.; Zuo, Y.; Guo, S.C. Genome-wide analysis of H3K36me3 and its regulations to cancer-related genes expression in human cell lines. Biosystems 2018, 171, 59–65. [Google Scholar] [CrossRef]
  45. García-Carpizo, V.; Sarmentero, J.; Han, B.; Graña, O.; Ruiz-Llorente, S.; Pisano, D.G.; Serrano, M.; Brooks, H.B.; Campbell, R.M.; Barrero, M.J. NSD2 contributes to oncogenic RAS-driven transcription in lung cancer cells through long-range epigenetic activation. Sci. Rep. 2016, 6, 32952. [Google Scholar] [CrossRef]
  46. Keats, J.J.; Maxwell, C.A.; Taylor, B.J.; Hendzel, M.J.; Chesi, M.; Bergsagel, P.L.; Larratt, L.M.; Mant, M.J.; Reiman, T.; Belch, A.R.; et al. Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients. Blood 2005, 105, 4060–4069. [Google Scholar] [CrossRef]
  47. Martinez-Garcia, E.; Popovic, R.; Min, D.J.; Sweet, S.M.M.; Thomas, P.M.; Zamdborg, L.; Heffner, A.; Will, C.; Lamy, L.; Staudt, L.M.; et al. The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood 2011, 117, 211–220. [Google Scholar] [CrossRef]
  48. Chesi, M.; Nardini, E.; Lim, R.S.; Smith, K.D.; Kuehl, W.M.; Bergsagel, P.L. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. Blood 1998, 92, 3025–3034. [Google Scholar] [CrossRef]
  49. Brito, J.L.R.; Walker, B.; Jenner, M.; Dickens, N.J.; Brown, N.J.M.; Ross, F.M.; Avramidou, A.; Irving, J.A.E.; Gonzalez, D.; Davies, F.E.; et al. MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells. Haematologica 2009, 94, 78–86. [Google Scholar] [CrossRef]
  50. Huang, Z.; Wu, H.; Chuai, S.; Xu, F.; Yan, F.; Englund, N.; Wang, Z.; Zhang, H.; Fang, M.; Wang, Y.; et al. NSD2 Is Recruited through Its PHD Domain to Oncogenic Gene Loci to Drive Multiple Myeloma. Cancer Res. 2013, 73, 6277–6288. [Google Scholar] [CrossRef] [Green Version]
  51. Lauring, J.; Abukhdeir, A.M.; Konishi, H.; Garay, J.P.; Gustin, J.P.; Wang, Q.; Arceci, R.J.; Matsui, W.; Park, B.H. The multiple myeloma associated MMSET gene contributes to cellular adhesion, clonogenic growth, and tumorigenicity. Blood 2008, 111, 856–864. [Google Scholar] [CrossRef]
  52. Sengupta, D.; Zeng, L.; Li, Y.; Li, W.; Mazur, P.K.; Hausmann, S.; Ghosh, D.; Yuan, G.; Nguyen, T.N.; Lyu, R.; et al. NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis. Mol. Cell 2021, 81, 4481–4492.e4489. [Google Scholar] [CrossRef]
  53. Lu, C.; Jain, S.U.; Hoelper, D.; Bechet, D.; Molden, R.C.; Ran, L.; Murphy, D.; Venneti, S.; Hameed, M.; Pawel, B.R.; et al. Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science 2016, 352, 844–849. [Google Scholar] [CrossRef]
  54. Aytes, A.; Giacobbe, A.; Mitrofanova, A.; Ruggero, K.; Cyrta, J.; Arriaga, J.; Palomero, L.; Farran-Matas, S.; Rubin, M.A.; Shen, M.M.; et al. NSD2 is a conserved driver of metastatic prostate cancer progression. Nat. Commun. 2018, 9, 5201. [Google Scholar] [CrossRef]
  55. Dillon, S.C.; Zhang, X.; Trievel, R.C.; Cheng, X. The SET-domain protein superfamily: Protein lysine methyltransferases. Genome Biol. 2005, 6, 227. [Google Scholar] [CrossRef]
  56. Herz, H.M.; Garruss, A.; Shilatifard, A. SET for life: Biochemical activities and biological functions of SET domain-containing proteins. Trends Biochem. Sci. 2013, 38, 621–639. [Google Scholar] [CrossRef]
  57. Barral, A.; Pozo, G.; Ducrot, L.; Papadopoulos, G.L.; Sauzet, S.; Oldfield, A.J.; Cavalli, G.; Déjardin, J. SETDB1/NSD-dependent H3K9me3/H3K36me3 dual heterochromatin maintains gene expression profiles by bookmarking poised enhancers. Mol. Cell 2022, 82, 816–832.e812. [Google Scholar] [CrossRef]
  58. Huang, C.; Zhu, B. Roles of H3K36-specific histone methyltransferases in transcription: Antagonizing silencing and safeguarding transcription fidelity. Biophys. Rep. 2018, 4, 170. [Google Scholar] [CrossRef]
  59. Baker, L.A.; Allis, C.D.; Wang, G.G. PHD fingers in human diseases: Disorders arising from misinterpreting epigenetic marks. Mutat. Res. 2008, 647, 3–12. [Google Scholar] [CrossRef] [PubMed]
  60. Pasillas, M.P.; Shah, M.; Kamps, M.P. NSD1 PHD domains bind methylated H3K4 and H3K9 using interactions disrupted by point mutations in human sotos syndrome. Hum. Mutat. 2011, 32, 292–298. [Google Scholar] [CrossRef] [PubMed]
  61. Sankaran, S.M.; Wilkinson, A.W.; Elias, J.E.; Gozani, O. A PWWP Domain of Histone-Lysine N-Methyltransferase NSD2 Binds to Dimethylated Lys-36 of Histone H3 and Regulates NSD2 Function at Chromatin. J. Biol. Chem. 2016, 291, 8465–8474. [Google Scholar] [CrossRef] [PubMed]
  62. Dilworth, D.; Hanley, R.P.; de Freitas, R.F.; Allali-Hassani, A.; Zhou, M.; Mehta, N.; Marunde, M.R.; Ackloo, S.; Marcon, E.; Li, F.; et al. Pharmacological targeting of a PWWP domain demonstrates cooperative control of NSD2 localization. bioRxiv 2021. [Google Scholar] [CrossRef]
  63. Qin, S.; Min, J. Structure and function of the nucleosome-binding PWWP domain. Trends Biochem. Sci. 2014, 39, 536–547. [Google Scholar] [CrossRef]
  64. Vermeulen, M.; Eberl, H.C.; Matarese, F.; Marks, H.; Denissov, S.; Butter, F.; Lee, K.K.; Olsen, J.V.; Hyman, A.A.; Stunnenberg, H.G.; et al. Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers. Cell 2010, 142, 967–980. [Google Scholar] [CrossRef]
  65. Nimura, K.; Ura, K.; Shiratori, H.; Ikawa, M.; Okabe, M.; Schwartz, R.J.; Kaneda, Y. A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature 2009, 460, 287–291. [Google Scholar] [CrossRef]
  66. Rayasam, G.V.; Wendling, O.; Angrand, P.O.; Mark, M.; Niederreither, K.; Song, L.; Lerouge, T.; Hager, G.L.; Chambon, P.; Losson, R. NSD1 is essential for early post-implantation development and has a catalytically active SET domain. EMBO J. 2003, 22, 3153–3163. [Google Scholar] [CrossRef]
  67. Jacques-Fricke, B.T.; Gammill, L.S. Neural crest specification and migration independently require NSD3-related lysine methyltransferase activity. Mol. Biol. Cell 2014, 25, 4174–4186. [Google Scholar] [CrossRef]
  68. Jacques-Fricke, B.T.; Roffers-Agarwal, J.; Hussein, A.O.; Yoder, K.J.; Gearhart, M.D.; Gammill, L.S. Profiling NSD3-dependent neural crest gene expression reveals known and novel candidate regulatory factors. Dev. Biol. 2021, 475, 118–130. [Google Scholar] [CrossRef]
  69. Kurotaki, N.; Imaizumi, K.; Harada, N.; Masuno, M.; Kondoh, T.; Nagai, T.; Ohashi, H.; Naritomi, K.; Tsukahara, M.; Makita, Y.; et al. Haploinsufficiency of NSD1 causes Sotos syndrome. Nat. Genet. 2002, 30, 365–366. [Google Scholar] [CrossRef]
  70. Bergemann, A.D.; Cole, F.; Hirschhorn, K. The etiology of Wolf-Hirschhorn syndrome. Trends Genet. TIG 2005, 21, 188–195. [Google Scholar] [CrossRef]
  71. Campos-Sanchez, E.; Deleyto-Seldas, N.; Dominguez, V.; Skok, J.A.; Luisa Martinez-Frias, M.; Correspondence, C.C. Wolf-Hirschhorn Syndrome Candidate 1 Is Necessary for Correct Hematopoietic and B Cell Development. Cell Rep. 2017, 19, 1586–1601. [Google Scholar] [CrossRef]
  72. Campos-Sanchez, E.; Martinez-Cano, J.; Del Pino Molina, L.; Lopez-Granados, E.; Cobaleda, C. Epigenetic Deregulation in Human Primary Immunodeficiencies. Trends Immunol. 2019, 40, 49–65. [Google Scholar] [CrossRef]
  73. Morishita, M.; Mevius, D.; Di Luccio, E. In vitro histone lysine methylation by NSD1, NSD2/MMSET/WHSC1 and NSD3/WHSC1L. BMC Struct. Biol. 2014, 14, 25. [Google Scholar] [CrossRef]
  74. Pei, H.; Zhang, L.; Luo, K.; Qin, Y.; Chesi, M.; Fei, F.; Bergsagel, P.L.; Wang, L.; You, Z.; Lou, Z. MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature 2011, 470, 124–129. [Google Scholar] [CrossRef]
  75. Huang, H.; Howard, C.A.; Zari, S.; Cho, H.J.; Shukla, S.; Li, H.; Ndoj, J.; Gonzalez-Alonso, P.; Nikolaidis, C.; Abbott, J.; et al. Covalent inhibition of NSD1 histone methyltransferase. Nat. Chem. Biol. 2020, 16, 1403–1410. [Google Scholar] [CrossRef]
  76. Qiao, Q.; Li, Y.; Chen, Z.; Wang, M.; Reinberg, D.; Xu, R.M. The structure of NSD1 reveals an autoregulatory mechanism underlying histone H3K36 methylation. J. Biol. Chem. 2011, 286, 8361–8368. [Google Scholar] [CrossRef]
  77. Graham, S.E.; Tweedy, S.E.; Carlson, H.A. Dynamic behavior of the post-SET loop region of NSD1: Implications for histone binding and drug development. Protein Sci. 2016, 25, 1021–1029. [Google Scholar] [CrossRef]
  78. Huether, R.; Dong, L.; Chen, X.; Wu, G.; Parker, M.; Wei, L.; Ma, J.; Edmonson, M.N.; Hedlund, E.K.; Rusch, M.C.; et al. The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat. Commun. 2014, 5, 3630. [Google Scholar] [CrossRef]
  79. Dobenecker, M.W.; Marcello, J.; Becker, A.; Rudensky, E.; Bhanu, N.V.; Carrol, T.; Garcia, B.A.; Prinjha, R.; Yurchenko, V.; Tarakhovsky, A. The catalytic domain of the histone methyltransferase NSD2/MMSET is required for the generation of B1 cells in mice. FEBS Lett. 2020, 594, 3324–3337. [Google Scholar] [CrossRef] [PubMed]
  80. Jaffe, J.D.; Wang, Y.; Chan, H.M.; Zhang, J.; Huether, R.; Kryukov, G.V.; Bhang, H.-E.C.; Taylor, J.E.; Hu, M.; Englund, N.P.; et al. Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia. Nat. Publ. Group 2013, 45, 1386–1391. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  81. Oyer, J.A.; Huang, X.; Zheng, Y.; Shim, J.; Ezponda, T.; Carpenter, Z.; Allegretta, M.; Okot-Kotber, C.I.; Patel, J.P.; Melnick, A.; et al. Point mutation E1099K in MMSET/NSD2 enhances its methyltranferase activity and leads to altered global chromatin methylation in lymphoid malignancies. Leukemia 2013, 28, 198–201. [Google Scholar] [CrossRef] [PubMed]
  82. Zhao, L.h.; Li, Q.; Huang, Z.J.; Sun, M.X.; Lu, J.j.; Zhang, X.h.; Li, G.; Wu, F. Identification of histone methyltransferase NSD2 as an important oncogenic gene in colorectal cancer. Cell Death Dis. 2021, 12, 974. [Google Scholar] [CrossRef] [PubMed]
  83. Cobaleda, C.; Vicente-Duenas, C.; Sanchez-Garcia, I. Infectious triggers and novel therapeutic opportunities in childhood B cell leukaemia. Nat. Rev. Immunol. 2021, 21, 570–581. [Google Scholar] [CrossRef] [PubMed]
  84. Pierro, J.; Saliba, J.; Narang, S.; Sethia, G.; Fleur-Lominy, S.S.; Chowdhury, A.; Qualls, A.; Fay, H.; Kilberg, H.L.; Moriyama, T.; et al. The NSD2 p.E1099K Mutation Is Enriched at Relapse and Confers Drug Resistance in a Cell Context-Dependent Manner in Pediatric Acute Lymphoblastic Leukemia. Mol. Cancer Res. MCR 2020, 18, 1153–1165. [Google Scholar] [CrossRef]
  85. Li, B.; Brady, S.W.; Ma, X.; Shen, S.; Zhang, Y.; Li, Y.; Szlachta, K.; Dong, L.; Liu, Y.; Yang, F.; et al. Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia. Blood 2020, 135, 41–55. [Google Scholar] [CrossRef]
  86. Ma, X.; Edmonson, M.; Yergeau, D.; Muzny, D.M.; Hampton, O.A.; Rusch, M.; Song, G.; Easton, J.; Harvey, R.C.; Wheeler, D.A.; et al. Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia. Nat. Commun. 2015, 6, 6604. [Google Scholar] [CrossRef]
  87. Li, W.; Tian, W.; Yuan, G.; Deng, P.; Sengupta, D.; Cheng, Z.; Cao, Y.; Ren, J.; Qin, Y.; Zhou, Y.; et al. Molecular basis of nucleosomal H3K36 methylation by NSD methyltransferases. Nature 2021, 590, 498–503. [Google Scholar] [CrossRef]
  88. Sato, K.; Kumar, A.; Hamada, K.; Okada, C.; Oguni, A.; Machiyama, A.; Sakuraba, S.; Nishizawa, T.; Nureki, O.; Kono, H.; et al. Structural basis of the regulation of the normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2. Nat. Commun. 2021, 12, 6605. [Google Scholar] [CrossRef]
  89. Swaroop, A.; Oyer, J.A.; Will, C.M.; Huang, X.; Yu, W.; Troche, C.; Bulic, M.; Durham, B.H.; Wen, Q.J.; Crispino, J.D.; et al. An activating mutation of the NSD2 histone methyltransferase drives oncogenic reprogramming in acute lymphocytic leukemia. Oncogene 2019, 38, 671–686. [Google Scholar] [CrossRef]
  90. Narang, S.; Evensen, N.; Saliba, J.; Pierro, J.; Loh, M.L.; Brown, P.A.; Mulder, H.; Shao, Y.; Easton, J.; Ma, X.; et al. NSD2 E1099K drives relapse in pediatric acute lymphoblastic leukemia by disrupting 3D chromatin organization. bioRxiv 2022. [Google Scholar] [CrossRef]
  91. Li, J.; Hlavka-Zhang, J.; Shrimp, J.H.; Piper, C.; Dupéré-Richér, D.; Roth, J.S.; Jing, D.; Casellas Román, H.L.; Troche, C.; Swaroop, A.; et al. PRC2 Inhibitors Overcome Glucocorticoid Resistance Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia. Cancer Discov. 2022, 12, 186–203. [Google Scholar] [CrossRef]
  92. Alzrigat, M.; Parraga, A.A.; Jernberg-Wiklund, H. Epigenetics in multiple myeloma: From mechanisms to therapy. Semin. Cancer Biol. 2018, 51, 101–115. [Google Scholar] [CrossRef]
  93. Hajdu, I.; Ciccia, A.; Lewis, S.M.; Elledge, S.J. Wolf–Hirschhorn syndrome candidate 1 is involved in the cellular response to DNA damage. Proc. Natl. Acad. Sci. USA 2011, 108, 13130–13134. [Google Scholar] [CrossRef]
  94. De Smedt, E.; Lui, H.; Maes, K.; De Veirman, K.; Menu, E.; Vanderkerken, K.; De Bruyne, E. The Epigenome in Multiple Myeloma: Impact on Tumor Cell Plasticity and Drug Response. Front. Oncol. 2018, 8, 566. [Google Scholar] [CrossRef]
  95. Min, D.J.; Ezponda, T.; Kim, M.K.; Will, C.M.; Martinez-Garcia, E.; Popovic, R.; Basrur, V.; Elenitoba-Johnson, K.S.; Licht, J.D. MMSET stimulates myeloma cell growth through microRNA-mediated modulation of c-MYC. Leukemia 2012, 27, 686–694. [Google Scholar] [CrossRef]
  96. Park, J.W.; Chae, Y.C.; Kim, J.Y.; Oh, H.; Seo, S.B. Methylation of Aurora kinase A by MMSET reduces p53 stability and regulates cell proliferation and apoptosis. Oncogene 2018, 37, 6212–6224. [Google Scholar] [CrossRef]
  97. Wu, S.P.; Pfeiffer, R.M.; Ahn, I.E.; Mailankody, S.; Sonneveld, P.; Duin, M.V.; Munshi, N.C.; Walker, B.A.; Morgan, G.; Landgren, O. Impact of Genes Highly Correlated with MMSET Myeloma on the Survival of Non-MMSET Myeloma Patients. Clin. Cancer Res. 2016, 22, 4039–4044. [Google Scholar] [CrossRef]
  98. Liu, J.; Xie, Y.; Guo, J.; Li, X.; Wang, J.; Jiang, H.; Peng, Z.; Wang, J.; Wang, S.; Li, Q.; et al. Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma. Nat. Commun. 2021, 12, 1022. [Google Scholar] [CrossRef]
  99. Agarwal, R.; Chan, Y.C.; Tam, C.S.; Hunter, T.; Vassiliadis, D.; Teh, C.E.; Thijssen, R.; Yeh, P.; Wong, S.Q.; Ftouni, S.; et al. Dynamic molecular monitoring reveals that SWI–SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma. Nat. Med. 2018, 25, 119–129. [Google Scholar] [CrossRef]
  100. Yang, P.; Zhang, W.; Wang, J.; Liu, Y.; An, R.; Jing, H. Genomic landscape and prognostic analysis of mantle cell lymphoma. Cancer Gene Ther. 2018, 25, 129–140. [Google Scholar] [CrossRef]
  101. Zhang, J.; Jima, D.; Moffitt, A.B.; Liu, Q.; Czader, M.; Hsi, E.D.; Fedoriw, Y.; Dunphy, C.H.; Richards, K.L.; Gill, J.I.; et al. The genomic landscape of mantle cell lymphoma is related to the epigenetically determined chromatin state of normal B cells. Blood 2014, 123, 2988–2996. [Google Scholar] [CrossRef]
  102. Beà, S.; Valdés-Mas, R.; Navarro, A.; Salaverria, I.; Martín-Garcia, D.; Jares, P.; Giné, E.; Pinyol, M.; Royo, C.; Nadeu, F.; et al. Landscape of somatic mutations and clonal evolution in mantle cell lymphoma. Proc. Natl. Acad. Sci. USA 2013, 110, 18250–18255. [Google Scholar] [CrossRef] [PubMed]
  103. Peng, X.; Peng, Q.; Zhong, L. Targeting H3K36 methyltransferases NSDs: A promising strategy for tumor targeted therapy. Signal. Transduct. Target. Ther. 2021, 6, 220. [Google Scholar] [CrossRef] [PubMed]
  104. Dong, Y.; Zhao, X.; Feng, X.; Zhou, Y.; Yan, X.; Zhang, Y.; Bu, J.; Zhan, D.; Hayashi, Y.; Zhang, Y.; et al. SETD2 mutations confer chemoresistance in acute myeloid leukemia partly through altered cell cycle checkpoints. Leukemia 2019, 33, 2585–2598. [Google Scholar] [CrossRef] [PubMed]
  105. De Deus Wagatsuma, V.M.; Pereira-Martins, D.A.; Do Nascimento, M.C.; Sanchez Mendoza, S.E.; Lucena-Araujo, A.R.; Lima, A.; Saldanha-Araujo, F.; Pitella, F.; Traina, F.; Madeira, M.I.A.; et al. NSD1 and NSD2 Transcriptional Levels Might Predict Clinical Outcome in AML Patients. Blood 2018, 132, 5257. [Google Scholar] [CrossRef]
  106. Leonards, K.; Almosailleakh, M.; Tauchmann, S.; Bagger, F.O.; Thirant, C.; Juge, S.; Bock, T.; Méreau, H.; Bezerra, M.F.; Tzankov, A.; et al. Nuclear interacting SET domain protein 1 inactivation impairs GATA1-regulated erythroid differentiation and causes erythroleukemia. Nat. Commun. 2020, 11, 2807. [Google Scholar] [CrossRef] [PubMed]
  107. Park, J.W.; Kang, J.Y.; Hahm, J.Y.; Kim, H.J.; Seo, S.B. Proteosomal degradation of NSD2 by BRCA1 promotes leukemia cell differentiation. Commun. Biol. 2020, 3, 462. [Google Scholar] [CrossRef]
  108. Consortium, A.P.G. AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov. 2017, 7, 818–831. [Google Scholar] [CrossRef]
  109. Bamford, S.; Dawson, E.; Forbes, S.; Clements, J.; Pettett, R.; Dogan, A.; Flanagan, A.; Teague, J.; Futreal, P.A.; Stratton, M.R.; et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br. J. Cancer 2004, 91, 355–358. [Google Scholar] [CrossRef]
  110. Hanley-Lopez, J.; Estabrooks, L.L.; Stiehm, E.R. Antibody deficiency in Wolf-Hirschhorn syndrome. J. Pediatrics 1998, 133, 141–143. [Google Scholar] [CrossRef]
  111. Barrie, E.S.; Alfaro, M.P.; Pfau, R.B.; Goff, M.J.; McBride, K.L.; Manickam, K.; Zmuda, E.J. De novo loss-of-function variants in NSD2 (WHSC1) associate with a subset of Wolf–Hirschhorn syndrome. Cold Spring Harb. Mol. Case Stud. 2019, 5, a004044. [Google Scholar] [CrossRef]
  112. Zanoni, P.; Steindl, K.; Sengupta, D.; Joset, P.; Bahr, A.; Sticht, H.; Lang-Muritano, M.; van Ravenswaaij-Arts, C.M.A.; Shinawi, M.; Andrews, M.; et al. Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype. Genet. Med. 2021, 23, 1474–1483. [Google Scholar] [CrossRef]
  113. Yu, C.; Yao, X.; Zhao, L.; Wang, P.; Zhang, Q.; Zhao, C.; Yao, S.; Wei, Y. Wolf-Hirschhorn Syndrome Candidate 1 (whsc1) Functions as a Tumor Suppressor by Governing Cell Differentiation. Neoplasia 2017, 19, 606–616. [Google Scholar] [CrossRef]
  114. Chang, Y.; Zhang, X.; Horton, J.R.; Upadhyay, A.K.; Spannhoff, A.; Liu, J.; Snyder, J.P.; Bedford, M.T.; Cheng, X. Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nat. Struct. Mol. Biol. 2009, 16, 312–317. [Google Scholar] [CrossRef]
  115. Takahashi, K.; Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126, 663–676. [Google Scholar] [CrossRef]
  116. Morishita, M.; Mevius, D.E.H.F.; Shen, Y.; Zhao, S.; di Luccio, E. BIX-01294 inhibits oncoproteins NSD1, NSD2 and NSD3. Med. Chem. Res. 2017, 26, 2038–2047. [Google Scholar] [CrossRef]
  117. Zheng, W.; Ibáñez, G.; Wu, H.; Blum, G.; Zeng, H.; Dong, A.; Li, F.; Hajian, T.; Allali-Hassani, A.; Amaya, M.F.; et al. Sinefungin derivatives as inhibitors and structure probes of protein lysine methyltransferase SETD2. J. Am. Chem. Soc. 2012, 134, 18004–18014. [Google Scholar] [CrossRef]
  118. Tisi, D.; Chiarparin, E.; Tamanini, E.; Pathuri, P.; Coyle, J.E.; Hold, A.; Holding, F.P.; Amin, N.; Martin, A.C.L.; Rich, S.J.; et al. Structure of the Epigenetic Oncogene MMSET and Inhibition by N-Alkyl Sinefungin Derivatives. ACS Chem. Biol. 2016, 11, 3093–3105. [Google Scholar] [CrossRef]
  119. Rogawski, D.S.; Grembecka, J.; Cierpicki, T. H3K36 methyltransferases as cancer drug targets: Rationale and perspectives for inhibitor development. Future Med. Chem. 2016, 8, 1589. [Google Scholar] [CrossRef]
  120. Rogawski, D.S.; Deng, J.; Li, H.; Miao, H.; Borkin, D.; Purohit, T.; Song, J.; Chase, J.; Li, S.; Ndoj, J.; et al. Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity. Nat. Commun. 2021, 12, 2792. [Google Scholar] [CrossRef]
  121. Morrison, M.J.; Ann, P.B.S.; Swinger, K.K.; Wigle, T.J.; Sadalge, D.; Kuntz, K.W.; Scott, M.P.; Janzen, W.P.; Chesworth, R.; Duncan, K.W.; et al. Identification of a peptide inhibitor for the histone methyltransferase WHSC1. PLoS ONE 2018, 13, e0197082. [Google Scholar] [CrossRef]
  122. Coussens, N.P.; Kales, S.C.; Henderson, M.J.; Lee, O.W.; Horiuchi, K.Y.; Wang, Y.; Chen, Q.; Kuznetsova, E.; Wu, J.; Chakka, S.; et al. High-throughput screening with nucleosome substrate identifies small-molecule inhibitors of the human histone lysine methyltransferase NSD2. J. Biol. Chem. 2018, 293, 13750–13765. [Google Scholar] [CrossRef]
  123. Luccio, E.D. Inhibition of Nuclear Receptor Binding SET Domain 2/Multiple Myeloma SET Domain by LEM-06 Implication for Epigenetic Cancer Therapies. J. Cancer Prev. 2015, 20, 113. [Google Scholar] [CrossRef]
  124. Shen, Y.; Morishita, M.; Lee, D.; Kim, S.; Lee, T.; Mevius, D.E.H.F.; Roh, Y.; di Luccio, E. Identification of LEM-14 inhibitor of the oncoprotein NSD2. Biochem. Biophys. Res. Commun. 2019, 508, 102–108. [Google Scholar] [CrossRef]
  125. Wang, S.; Yang, H.; Su, M.; Lian, F.; Cong, Z.; Wei, R.; Zhou, Y.; Li, X.; Zheng, X.; Li, C.; et al. 5-Aminonaphthalene derivatives as selective nonnucleoside nuclear receptor binding SET domain-protein 2 (NSD2) inhibitors for the treatment of multiple myeloma. Eur. J. Med. Chem. 2021, 222, 113592. [Google Scholar] [CrossRef] [PubMed]
  126. Bottcher, J.; Dilworth, D.; Reiser, U.; Neumuller, R.A.; Schleicher, M.; Petronczki, M.; Zeeb, M.; Mischerikow, N.; Allali-Hassani, A.; Szewczyk, M.M.; et al. Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3. Nat. Chem. Biol. 2019, 15, 822–829. [Google Scholar] [CrossRef] [PubMed]
  127. Ferreira de Freitas, R.; Liu, Y.; Szewczyk, M.M.; Mehta, N.; Li, F.; McLeod, D.; Zepeda-Velazquez, C.; Dilworth, D.; Hanley, R.P.; Gibson, E.; et al. Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2. J. Med. Chem. 2021, 64, 1584–1592. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Schematic representation of NSD family proteins basic structure: PWWP, methylation-binding domain; PHD, Plant HomeoDomain; SET, histone methyl transferase domain; AWS, domain associated with the SET domain.
Figure 1. Schematic representation of NSD family proteins basic structure: PWWP, methylation-binding domain; PHD, Plant HomeoDomain; SET, histone methyl transferase domain; AWS, domain associated with the SET domain.
Ijms 23 11075 g001
Figure 2. Genetic alterations of NSD2 associated with hematological diseases. Point mutations at the SET catalytic domain and chromosome aberrations are indicated. Hematological malignancies (B cell acute leukemia, mantle B cell lymphoma, and multiple myeloma) are mainly associated with NSD2 gain of function (GOF) alterations, while developmental disorders (Rauch–Steindl syndrome and Wolf–Hirschhorn syndrome) are associated with NSD2 loss of function (LOF) alterations.
Figure 2. Genetic alterations of NSD2 associated with hematological diseases. Point mutations at the SET catalytic domain and chromosome aberrations are indicated. Hematological malignancies (B cell acute leukemia, mantle B cell lymphoma, and multiple myeloma) are mainly associated with NSD2 gain of function (GOF) alterations, while developmental disorders (Rauch–Steindl syndrome and Wolf–Hirschhorn syndrome) are associated with NSD2 loss of function (LOF) alterations.
Ijms 23 11075 g002
Table 1. NSD2 inhibitors and therapeutic strategies.
Table 1. NSD2 inhibitors and therapeutic strategies.
CompoundChemical NameSpecific TargetTherapeutic AplicationReferences
BIX-01294(1H-1,4-diazepin-1-yl)-quinazolin-4-yl amine derivativeGLP and NSD SET domainInduces cell autophagy (antitumor activity).[114,115,116]
Sinefungindelta-(5’-adenosyl) derivative of ornithine (natural compound)SETD2 and NSD2Antiparasitic agent.
Potential antitumor activity.
[118]
PTD2(Norleucine-containing peptide)NSD2Multiple myeloma treatment[121]
Chaetocin14-(hydroxymethyl)-3-[14-(hydroxymethyl)-18-methyl-13,17-dioxo-15,16-dithia-10,12,18-triazapentacyclo[12.2.2.01,12.03,11.04,9]octadeca-4,6,8-trien-3-yl]-18-methyl-15,16-dithia-10,12,18-triazapentacyclo[12.2.2.01,12.03,11.04,9]octadeca-4,6,8-triene-13,17-dione
Piperazine (fungal myotoxin)
NSD2 (mutated and WT forms), G9a and SU(VAR)3-9)Potential antitumor activity[122]
LEM-06
LEM-14
N-Cyclopropyl-3-oxo-N-(4-pyrimidin-4-ylcarbamoyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamideNSD2
(NSD1/3 weak)
Antitumor activity (specially multiple myeloma)[124]
9cAmino-N-benzylnaphthalene-1-sulfonamide hydrochlorideNSD2 catalytic domainMultiple myeloma and ALL[125]
UNC6934N-Cyclopropyl-3-oxo-N-(4-(pyrimidin-4-ylcarbamoyl)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamideNSD2 PWWP1 domainPotential antitumor activity. Disrupts chromatin–protein interaction[127]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Azagra, A.; Cobaleda, C. NSD2 as a Promising Target in Hematological Disorders. Int. J. Mol. Sci. 2022, 23, 11075. https://doi.org/10.3390/ijms231911075

AMA Style

Azagra A, Cobaleda C. NSD2 as a Promising Target in Hematological Disorders. International Journal of Molecular Sciences. 2022; 23(19):11075. https://doi.org/10.3390/ijms231911075

Chicago/Turabian Style

Azagra, Alba, and César Cobaleda. 2022. "NSD2 as a Promising Target in Hematological Disorders" International Journal of Molecular Sciences 23, no. 19: 11075. https://doi.org/10.3390/ijms231911075

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop