International Journal of Molecular Sciences

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7 pages, 523 KiB

Open AccessEditorial

Molecular Mechanisms and Therapies of Myeloid Leukaemia

by Elliott Brown and Barbara-ann Guinn

Int. J. Mol. Sci. 2022, 23(11), 6251; https://doi.org/10.3390/ijms23116251 - 2 Jun 2022

Cited by 1 | Viewed by 2706

Abstract

Acute myeloid leukaemia (AML) is defined as a malignant disorder of the bone marrow (BM) that is characterised by the clonal expansion and differentiation arrest of myeloid progenitor cells [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia)

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Research

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21 pages, 9690 KiB

Open AccessArticle

BCL-2 Inhibitor ABT-737 Effectively Targets Leukemia-Initiating Cells with Differential Regulation of Relevant Genes Leading to Extended Survival in a NRAS/BCL-2 Mouse Model of High Risk-Myelodysplastic Syndrome

by Petra Gorombei, Fabien Guidez, Saravanan Ganesan, Mathieu Chiquet, Andrea Pellagatti, Laure Goursaud, Nilgun Tekin, Stephanie Beurlet, Satyananda Patel, Laura Guerenne, Carole Le Pogam, Niclas Setterblad, Pierre de la Grange, Christophe LeBoeuf, Anne Janin, Maria-Elena Noguera, Laure Sarda-Mantel, Pascale Merlet, Jacqueline Boultwood, Marina Konopleva, Michael Andreeff, Robert West, Marika Pla, Lionel Adès, Pierre Fenaux, Patricia Krief, Christine Chomienne, Nader Omidvar and Rose Ann Padua Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(19), 10658; https://doi.org/10.3390/ijms221910658 - 30 Sep 2021

Cited by 8 | Viewed by 3085

Abstract

During transformation, myelodysplastic syndromes (MDS) are characterized by reducing apoptosis of bone marrow (BM) precursors. Mouse models of high risk (HR)-MDS and acute myelogenous leukemia (AML) post-MDS using mutant NRAS and overexpression of human BCL-2, known to be poor prognostic indicators of the [...] Read more.

During transformation, myelodysplastic syndromes (MDS) are characterized by reducing apoptosis of bone marrow (BM) precursors. Mouse models of high risk (HR)-MDS and acute myelogenous leukemia (AML) post-MDS using mutant NRAS and overexpression of human BCL-2, known to be poor prognostic indicators of the human diseases, were created. We have reported the efficacy of the BCL-2 inhibitor, ABT-737, on the AML post-MDS model; here, we report that this BCL-2 inhibitor also significantly extended survival of the HR-MDS mouse model, with reductions of BM blasts and lineage negative/Sca1+/KIT+ (LSK) cells. Secondary transplants showed increased survival in treated compared to untreated mice. Unlike the AML model, BCL-2 expression and RAS activity decreased following treatment and the RAS:BCL-2 complex remained in the plasma membrane. Exon-specific gene expression profiling (GEP) of HR-MDS mice showed 1952 differentially regulated genes upon treatment, including genes important for the regulation of stem cells, differentiation, proliferation, oxidative phosphorylation, mitochondrial function, and apoptosis; relevant in human disease. Spliceosome genes, found to be abnormal in MDS patients and downregulated in our HR-MDS model, such as Rsrc1 and Wbp4, were upregulated by the treatment, as were genes involved in epigenetic regulation, such as DNMT3A and B, upregulated upon disease progression and downregulated upon treatment. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia)

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21 pages, 2919 KiB

Open AccessArticle

Piceatannol, a Structural Analog of Resveratrol, Is an Apoptosis Inducer and a Multidrug Resistance Modulator in HL-60 Human Acute Myeloid Leukemia Cells

by Kamila Siedlecka-Kroplewska, Agata Wrońska and Zbigniew Kmieć

Int. J. Mol. Sci. 2021, 22(19), 10597; https://doi.org/10.3390/ijms221910597 - 30 Sep 2021

Cited by 11 | Viewed by 2814

Abstract

Acute myeloid leukemia is characterized by uncontrolled clonal proliferation of abnormal myeloid progenitor cells. Despite recent advances in the treatment of this disease, the prognosis and overall long-term survival for patients remain poor, which drives the search for new chemotherapeutics and treatment strategies. [...] Read more.

Acute myeloid leukemia is characterized by uncontrolled clonal proliferation of abnormal myeloid progenitor cells. Despite recent advances in the treatment of this disease, the prognosis and overall long-term survival for patients remain poor, which drives the search for new chemotherapeutics and treatment strategies. Piceatannol, a polyphenolic compound present in grapes and wine, appears to be a promising chemotherapeutic agent in the treatment of leukemia. The aim of the present study was to examine whether piceatannol induces autophagy and/or apoptosis in HL-60 human acute myeloid leukemia cells and whether HL-60 cells are able to acquire resistance to piceatannol toxicity. We found that piceatannol at the IC₉₀ concentration of 14 µM did not induce autophagy in HL-60 cells. However, it induced caspase-dependent apoptosis characterized by phosphatidylserine externalization, disruption of the mitochondrial membrane potential, caspase-3 activation, internucleosomal DNA fragmentation, PARP1 cleavage, chromatin condensation, and fragmentation of cell nuclei. Our findings also imply that HL-60 cells are able to acquire resistance to piceatannol toxicity via mechanisms related to MRP1 activity. Our results suggest that the use of piceatannol as a potential chemotherapeutic agent may be associated with the risk of multidrug resistance, warranting its use in combination with other chemotherapeutic agents. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia)

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14 pages, 2183 KiB

Open AccessArticle

Survivin’ Acute Myeloid Leukaemia—A Personalised Target for inv(16) Patients

by Jochen Greiner, Elliott Brown, Lars Bullinger, Robert K. Hills, Vanessa Morris, Hartmut Döhner, Ken I. Mills and Barbara-ann Guinn

Int. J. Mol. Sci. 2021, 22(19), 10482; https://doi.org/10.3390/ijms221910482 - 28 Sep 2021

Cited by 7 | Viewed by 3399

Abstract

Despite recent advances in therapies including immunotherapy, patients with acute myeloid leukaemia (AML) still experience relatively poor survival rates. The Inhibition of Apoptosis (IAP) family member, survivin, also known by its gene and protein name, Baculoviral IAP Repeat Containing 5 (BIRC5), remains one [...] Read more.

Despite recent advances in therapies including immunotherapy, patients with acute myeloid leukaemia (AML) still experience relatively poor survival rates. The Inhibition of Apoptosis (IAP) family member, survivin, also known by its gene and protein name, Baculoviral IAP Repeat Containing 5 (BIRC5), remains one of the most frequently expressed antigens across AML subtypes. To better understand its potential to act as a target for immunotherapy and a biomarker for AML survival, we examined the protein and pathways that BIRC5 interacts with using the Kyoto Encyclopedia of Genes and Genomes (KEGG), search tool for recurring instances of neighbouring genes (STRING), WEB-based Gene Set Analysis Toolkit, Bloodspot and performed a comprehensive literature review. We then analysed data from gene expression studies. These included 312 AML samples in the Microarray Innovations In Leukemia (MILE) dataset. We found a trend between above median levels of BIRC5 being associated with improved overall survival (OS) but this did not reach statistical significance (p = 0.077, Log-Rank). There was some evidence of a beneficial effect in adjusted analyses where above median levels of BIRC5 were shown to be associated with improved OS (p = 0.001) including in Core Binding Factor (CBF) patients (p = 0.03). Above median levels of BIRC5 transcript were associated with improved relapse free survival (p < 0.0001). Utilisation of a second large cDNA microarray dataset including 306 AML cases, again showed no correlation between BIRC5 levels and OS, but high expression levels of BIRC5 correlated with worse survival in inv(16) patients (p = 0.077) which was highly significant when datasets A and B were combined (p = 0.001). In addition, decreased BIRC5 expression was associated with better clinical outcome (p = 0.004) in AML patients exhibiting CBF mainly due to patients with inv(16) (p = 0.007). This study has shown that BIRC5 expression plays a role in the survival of AML patients, this association is not apparent when we examine CBF patients as a cohort, but when those with inv(16) independently indicating that those patients with inv(16) would provide interesting candidates for immunotherapies that target BIRC5. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia)

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18 pages, 5774 KiB

Open AccessArticle

Multiplex Screening for Interacting Compounds in Paediatric Acute Myeloid Leukaemia

by Lauren V. Cairns, Katrina M. Lappin, Alexander Mutch, Ahlam Ali, Kyle B. Matchett and Ken I. Mills

Int. J. Mol. Sci. 2021, 22(18), 10163; https://doi.org/10.3390/ijms221810163 - 21 Sep 2021

Cited by 1 | Viewed by 2899

Abstract

Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the malignant transformation of myeloid precursor cells with impaired differentiation. Standard therapy for paediatric AML has remained largely unchanged for over four decades and, combined with inadequate understanding of the biology of [...] Read more.

Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the malignant transformation of myeloid precursor cells with impaired differentiation. Standard therapy for paediatric AML has remained largely unchanged for over four decades and, combined with inadequate understanding of the biology of paediatric AML, has limited the progress of targeted therapies in this cohort. In recent years, the search for novel targets for the treatment of paediatric AML has accelerated in parallel with advanced genomic technologies which explore the mutational and transcriptional landscape of this disease. Exploiting the large combinatorial space of existing drugs provides an untapped resource for the identification of potential combination therapies for the treatment of paediatric AML. We have previously designed a multiplex screening strategy known as Multiplex Screening for Interacting Compounds in AML (MuSICAL); using an algorithm designed in-house, we screened all pairings of 384 FDA-approved compounds in less than 4000 wells by pooling drugs into 10 compounds per well. This approach maximised the probability of identifying new compound combinations with therapeutic potential while minimising cost, replication and redundancy. This screening strategy identified the triple combination of glimepiride, a sulfonylurea; pancuronium dibromide, a neuromuscular blocking agent; and vinblastine sulfate, a vinca alkaloid, as a potential therapy for paediatric AML. We envision that this approach can be used for a variety of disease-relevant screens allowing the efficient repurposing of drugs that can be rapidly moved into the clinic. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia)

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17 pages, 2648 KiB

Open AccessArticle

NUP-98 Rearrangements Led to the Identification of Candidate Biomarkers for Primary Induction Failure in Pediatric Acute Myeloid Leukemia

by Vincenza Barresi, Virginia Di Bella, Nellina Andriano, Anna Provvidenza Privitera, Paola Bonaccorso, Manuela La Rosa, Valeria Iachelli, Giorgia Spampinato, Giulio Pulvirenti, Chiara Scuderi, Daniele F. Condorelli and Luca Lo Nigro

Int. J. Mol. Sci. 2021, 22(9), 4575; https://doi.org/10.3390/ijms22094575 - 27 Apr 2021

Cited by 11 | Viewed by 3054

Abstract

Conventional chemotherapy for acute myeloid leukemia regimens generally encompass an intensive induction phase, in order to achieve a morphological remission in terms of bone marrow blasts (<5%). The majority of cases are classified as Primary Induction Response (PIR); unfortunately, 15% of children do [...] Read more.

Conventional chemotherapy for acute myeloid leukemia regimens generally encompass an intensive induction phase, in order to achieve a morphological remission in terms of bone marrow blasts (<5%). The majority of cases are classified as Primary Induction Response (PIR); unfortunately, 15% of children do not achieve remission and are defined Primary Induction Failure (PIF). This study aims to characterize the gene expression profile of PIF in children with Acute Myeloid Leukemia (AML), in order to detect molecular pathways dysfunctions and identify potential biomarkers. Given that NUP98-rearrangements are enriched in PIF-AML patients, we investigated the association of NUP98-driven genes in primary chemoresistance. Therefore, 85 expression arrays, deposited on GEO database, and 358 RNAseq AML samples, from TARGET program, were analyzed for “Differentially Expressed Genes” (DEGs) between NUP98+ and NUP98-, identifying 110 highly confident NUP98/PIF-associated DEGs. We confirmed, by qRT-PCR, the overexpression of nine DEGs, selected on the bases of the diagnostic accuracy, in a local cohort of PIF patients: SPINK2, TMA7, SPCS2, CDCP1, CAPZA1, FGFR1OP2, MAN1A2, NT5C3A and SRP54. In conclusion, the integrated analysis of NUP98 mutational analysis and transcriptome profiles allowed the identification of novel putative biomarkers for the prediction of PIF in AML. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia)

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Review

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18 pages, 2278 KiB

Open AccessReview

Increasing Role of Targeted Immunotherapies in the Treatment of AML

by Jochen Greiner, Marlies Götz and Verena Wais

Int. J. Mol. Sci. 2022, 23(6), 3304; https://doi.org/10.3390/ijms23063304 - 18 Mar 2022

Cited by 10 | Viewed by 3450

Abstract

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. The standard of care in medically and physically fit patients is intensive induction therapy. The majority of these intensively treated patients achieve a complete remission. However, a high number of these [...] Read more.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. The standard of care in medically and physically fit patients is intensive induction therapy. The majority of these intensively treated patients achieve a complete remission. However, a high number of these patients will experience relapse. In patients older than 60 years, the results are even worse. Therefore, new therapeutic approaches are desperately needed. One promising approach in high-risk leukemia to prevent relapse is the induction of the immune system simultaneously or after reduction of the initial tumor burden. Different immunotherapeutic approaches such as allogenic stem cell transplantation or donor lymphocyte infusions are already standard therapies, but other options for AML treatment are in the pipeline. Moreover, the therapeutic landscape in AML is rapidly changing, and in the last years, a number of immunogenic targets structures eligible for specific therapy, risk assessment or evaluation of disease course were determined. For example, leukemia-associated antigens (LAA) showed to be critical as biomarkers of disease state and survival, as well as markers of minimal residual disease (MRD). Yet many mechanisms and properties are still insufficiently understood, which also represents a great potential for this form of therapy. Therefore, targeted therapy as immunotherapy could turn into an efficient tool to clear residual disease, improve the outcome of AML patients and reduce the relapse risk. In this review, established but also emerging immunotherapeutic approaches for AML patients will be discussed. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia)

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16 pages, 1846 KiB

Open AccessReview

Significance of NPM1 Gene Mutations in AML

by Andrew Hindley, Mark Alexander Catherwood, Mary Frances McMullin and Ken I. Mills

Int. J. Mol. Sci. 2021, 22(18), 10040; https://doi.org/10.3390/ijms221810040 - 17 Sep 2021

Cited by 26 | Viewed by 8541

Abstract

The aim of this literature review is to examine the significance of the nucleophosmin 1 (NPM1) gene in acute myeloid leukaemia (AML). This will include analysis of the structure and normal cellular function of NPM1, the type of mutations commonly witnessed [...] Read more.

The aim of this literature review is to examine the significance of the nucleophosmin 1 (NPM1) gene in acute myeloid leukaemia (AML). This will include analysis of the structure and normal cellular function of NPM1, the type of mutations commonly witnessed in NPM1, and the mechanism by which this influences the development and progression of AML. The importance of NPM1 mutation on prognosis and the treatment options available to patients will also be reviewed along with current guidelines recommending the rapid return of NPM1 mutational screening results and the importance of employing a suitable laboratory assay to achieve this. Finally, future developments in the field including research into new therapies targeting NPM1 mutated AML are considered. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia)

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19 pages, 2507 KiB

Open AccessReview

The Impact of Epigenetic Modifications in Myeloid Malignancies

by Deirdra Venney, Adone Mohd-Sarip and Ken I Mills

Int. J. Mol. Sci. 2021, 22(9), 5013; https://doi.org/10.3390/ijms22095013 - 9 May 2021

Cited by 17 | Viewed by 5085

Abstract

Myeloid malignancy is a broad term encapsulating myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Initial studies into genomic profiles of these diseases have shown 2000 somatic mutations prevalent across the spectrum of myeloid blood disorders. Epigenetic mutations are emerging [...] Read more.

Myeloid malignancy is a broad term encapsulating myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Initial studies into genomic profiles of these diseases have shown 2000 somatic mutations prevalent across the spectrum of myeloid blood disorders. Epigenetic mutations are emerging as critical components of disease progression, with mutations in genes controlling chromatin regulation and methylation/acetylation status. Genes such as DNA methyltransferase 3A (DNMT3A), ten eleven translocation methylcytosine dioxygenase 2 (TET2), additional sex combs-like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2) and isocitrate dehydrogenase 1/2 (IDH1/2) show functional impact in disease pathogenesis. In this review we discuss how current knowledge relating to disease progression, mutational profile and therapeutic potential is progressing and increasing understanding of myeloid malignancies. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia)

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