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Advanced Research in Acute Myeloid Leukemia
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Advanced Research in Acute Myeloid Leukemia

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 22245

Special Issue Editors

Dr. María Teresa Gómez-Casares

E-Mail Website
Guest Editor
Hematology Department, Hospital Universitario de Gran Canaria Dr. Negrín, 35019 Las Palmas, Spain
Interests: myelofibrosis; molecular screening; next-generation sequencing; prognostic risk stratification; myeproliferative neoplasms; myeloid and hematopoeitic diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Ruth Stuckey

E-Mail Website
Guest Editor
Hematology Department, Hospital Universitario de Gran Canaria Dr. Negrín, 35019 Las Palmas, Spain
Interests: molecular biology; next-generation sequencing; acute myeloid leukemia; molecular basis of cancer; genomic instability
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Advanced Research in acute myeloid leukemia (AML) genomics are revealing the broad biological heterogeneity of the disease, leading to new risk stratification models and targeted therapies for the more personalized monitoring and management of patients with AML. However, despite this progress, approximately 85% of AML patients will relapse within two to three years.

In this Special Issue we are particularly interested in original papers and review articles that advance our biological understanding of acute myeloid leukemia, including papers that:

  • Investigate how the bone marrow microenvironment and clonal dynamics of the leukemic stem cell (LSC) population influence AML development and relapse;
  • Elucidate the impact of clonal hematopoiesis in AML development and response to therapies;
  • Elucidate new molecular mechanisms with a role in AML or present novel biomarkers with prognostic value or clinical application in the near future.

Dr. María Teresa Gómez-Casares
Dr. Ruth Stuckey
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • molecular pathogenesis
  • leukemic stem cells
  • clonal evolution
  • clonal hematopoiesis
  • stem cell niche
  • directed therapies

Published Papers (7 papers)

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Research

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28 pages, 4698 KiB  
Article
Roles of Glutathione and AP-1 in the Enhancement of Vitamin D-Induced Differentiation by Activators of the Nrf2 Signaling Pathway in Acute Myeloid Leukemia Cells
by Yasmeen Jramne-Saleem and Michael Danilenko
Int. J. Mol. Sci. 2024, 25(4), 2284; https://doi.org/10.3390/ijms25042284 - 14 Feb 2024
Viewed by 839
Abstract
Active vitamin D derivatives (VDDs)—1α,25-dihydroxyvitamin D3/D2 and their synthetic analogs—are well-known inducers of cell maturation with the potential for differentiation therapy of acute myeloid leukemia (AML). However, their dose-limiting calcemic activity is a significant obstacle to using VDDs as an [...] Read more.
Active vitamin D derivatives (VDDs)—1α,25-dihydroxyvitamin D3/D2 and their synthetic analogs—are well-known inducers of cell maturation with the potential for differentiation therapy of acute myeloid leukemia (AML). However, their dose-limiting calcemic activity is a significant obstacle to using VDDs as an anticancer treatment. We have shown that different activators of the NF-E2-related factor-2/Antioxidant Response Element (Nrf2/ARE) signaling pathway, such as the phenolic antioxidant carnosic acid (CA) or the multiple sclerosis drug monomethyl fumarate (MMF), synergistically enhance the antileukemic effects of various VDDs applied at low concentrations in vitro and in vivo. This study aimed to investigate whether glutathione, the major cellular antioxidant and the product of the Nrf2/ARE pathway, can mediate the Nrf2-dependent differentiation-enhancing activity of CA and MMF in HL60 human AML cells. We report that glutathione depletion using L-buthionine sulfoximine attenuated the enhancing effects of both Nrf2 activators concomitant with downregulating vitamin D receptor (VDR) target genes and the activator protein-1 (AP-1) family protein c-Jun levels and phosphorylation. On the other hand, adding reduced glutathione ethyl ester to dominant negative Nrf2-expressing cells restored both the suppressed differentiation responses and the downregulated expression of VDR protein, VDR target genes, as well as c-Jun and P-c-Jun levels. Finally, using the transcription factor decoy strategy, we demonstrated that AP-1 is necessary for the enhancement by CA and MMF of 1α,25-dihydroxyvitamin D3-induced VDR and RXRα protein expression, transactivation of the vitamin D response element, and cell differentiation. Collectively, our findings suggest that glutathione mediates, at least in part, the potentiating effect of Nrf2 activators on VDDs-induced differentiation of AML cells, likely through the positive regulation of AP-1. Full article
(This article belongs to the Special Issue Advanced Research in Acute Myeloid Leukemia)
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21 pages, 5641 KiB  
Article
Cytoplasmic Expression of TP53INP2 Modulated by Demethylase FTO and Mutant NPM1 Promotes Autophagy in Leukemia Cells
by Junpeng Huang, Minghui Sun, Yonghong Tao, Jun Ren, Meixi Peng, Yipei Jing, Qiaoling Xiao, Jing Yang, Can Lin, Li Lei, Zailin Yang and Ling Zhang
Int. J. Mol. Sci. 2023, 24(2), 1624; https://doi.org/10.3390/ijms24021624 - 13 Jan 2023
Cited by 11 | Viewed by 2583
Abstract
Acute myeloid leukemia (AML) with a nucleophosmin 1 (NPM1) mutation is a unique subtype of adult leukemia. Recent studies show that NPM1-mutated AML has high autophagy activity. However, the mechanism for upholding the high autophagic level is still not fully [...] Read more.
Acute myeloid leukemia (AML) with a nucleophosmin 1 (NPM1) mutation is a unique subtype of adult leukemia. Recent studies show that NPM1-mutated AML has high autophagy activity. However, the mechanism for upholding the high autophagic level is still not fully elucidated. In this study, we first identified that tumor protein p53 inducible nuclear protein 2 (TP53INP2) was highly expressed and cytoplasmically localized in NPM1-mutated AML cells. Subsequent data showed that the expression of TP53INP2 was upregulated by fat mass and obesity-associated protein (FTO)-mediated m6A modification. Meanwhile, TP53INP2 was delocalized to the cytoplasm by interacting with NPM1 mutants. Functionally, cytoplasmic TP53INP2 enhanced autophagy activity by promoting the interaction of microtubule-associated protein 1 light chain 3 (LC3) - autophagy-related 7 (ATG7) and further facilitated the survival of leukemia cells. Taken together, our study indicates that TP53INP2 plays an oncogenic role in maintaining the high autophagy activity of NPM1-mutated AML and provides further insight into autophagy-targeted therapy of this leukemia subtype. Full article
(This article belongs to the Special Issue Advanced Research in Acute Myeloid Leukemia)
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11 pages, 1993 KiB  
Communication
RUNX1/CEBPA Mutation in Acute Myeloid Leukemia Promotes Hypermethylation and Indicates for Demethylation Therapy
by Ekaterina I. Romanova, Anatoliy V. Zubritskiy, Anna V. Lioznova, Adewale J. Ogunleye, Vasily A. Golotin, Anna A. Guts, Andreas Lennartsson, Oleg N. Demidov and Yulia A. Medvedeva
Int. J. Mol. Sci. 2022, 23(19), 11413; https://doi.org/10.3390/ijms231911413 - 27 Sep 2022
Cited by 7 | Viewed by 2550
Abstract
Acute myeloid leukemia (AML) is a rapidly progressing heterogeneous disease with a high mortality rate, which is characterized by hyperproliferation of atypical immature myeloid cells. The number of AML patients is expected to increase in the near future, due to the old-age-associated nature [...] Read more.
Acute myeloid leukemia (AML) is a rapidly progressing heterogeneous disease with a high mortality rate, which is characterized by hyperproliferation of atypical immature myeloid cells. The number of AML patients is expected to increase in the near future, due to the old-age-associated nature of AML and increased longevity in the human population. RUNX1 and CEBPA, key transcription factors (TFs) of hematopoiesis, are frequently and independently mutated in AML. RUNX1 and CEBPA can bind TET2 demethylase and attract it to their binding sites (TFBS) in cell lines, leading to DNA demethylation of the regions nearby. Since TET2 does not have a DNA-binding domain, TFs are crucial for its guidance to target genomic locations. In this paper, we show that RUNX1 and CEBPA mutations in AML patients affect the methylation of important regulatory sites that resulted in the silencing of several RUNX1 and CEBPA target genes, most likely in a TET2-dependent manner. We demonstrated that hypermethylation of TFBS in AML cells with RUNX1 mutations was associated with resistance to anticancer chemotherapy. Demethylation therapy restored expression of the RUNX1 target gene, BIK, and increased sensitivity of AML cells to chemotherapy. If our results are confirmed, mutations in RUNX1 could be an indication for prescribing the combination of cytotoxic and demethylation therapies. Full article
(This article belongs to the Special Issue Advanced Research in Acute Myeloid Leukemia)
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12 pages, 3037 KiB  
Article
Investigation of Biomarkers Associated with Low Platelet Counts in Normal Karyotype Acute Myeloid Leukemia
by Chang-Hun Park and Jae Won Yun
Int. J. Mol. Sci. 2022, 23(14), 7772; https://doi.org/10.3390/ijms23147772 - 14 Jul 2022
Cited by 3 | Viewed by 1828
Abstract
Acute myeloid leukemia (AML) patients are at risk of bleeding due to disease-related lack of platelets and systemic coagulopathy. Platelets play a role in hemostasis. Leukemic blasts have been shown to alter platelet activation in vitro. Here we investigated biomarkers associated with thrombocytopenia [...] Read more.
Acute myeloid leukemia (AML) patients are at risk of bleeding due to disease-related lack of platelets and systemic coagulopathy. Platelets play a role in hemostasis. Leukemic blasts have been shown to alter platelet activation in vitro. Here we investigated biomarkers associated with thrombocytopenia in normal karyotype AML (NK-AML). From The Cancer Genome Atlas database, case-control study was performed between normal karyotype (NK) platelet-decreased AML (PD-AML, platelet count < 100 × 109/L, n = 24) and NK platelet-not-decreased AML (PND-AML, with platelet count ≥ 100 × 109/L, n = 13). Differentially expressed gene analysis, pathway analysis and modelling for predicting platelet decrease in AML were performed. DEG analysis and pathway analysis revealed 157 genes and eight pathways specific for PD-AML, respectively. Most of the eight pathways were significantly involved in G-protein-coupled receptor-related pathway, cytokine-related pathway, and bone remodeling pathway. Among the key genes involved in at least one pathway, three genes including CSF1R, TNFSF15 and CLEC10A were selected as promising biomarkers for predicting PD-AML (0.847 of AUC in support vector machine model). This is the first study that identified biomarkers using RNA expression data analysis and could help understand the pathophysiology in AML with low platelet count. Full article
(This article belongs to the Special Issue Advanced Research in Acute Myeloid Leukemia)
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Review

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17 pages, 606 KiB  
Review
Biomarkers of Response to Venetoclax Therapy in Acute Myeloid Leukemia
by Carlos Rodríguez-Medina, Ruth Stuckey, Cristina Bilbao-Sieyro and María Teresa Gómez-Casares
Int. J. Mol. Sci. 2024, 25(3), 1421; https://doi.org/10.3390/ijms25031421 - 24 Jan 2024
Viewed by 1866
Abstract
Recent progress in the use of massive sequencing technologies has greatly enhanced our understanding of acute myeloid leukemia (AML) pathology. This knowledge has in turn driven the development of targeted therapies, such as venetoclax, a BCL-2 inhibitor approved for use in combination with [...] Read more.
Recent progress in the use of massive sequencing technologies has greatly enhanced our understanding of acute myeloid leukemia (AML) pathology. This knowledge has in turn driven the development of targeted therapies, such as venetoclax, a BCL-2 inhibitor approved for use in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of newly diagnosed adult patients with AML who are not eligible for intensive chemotherapy. However, a significant number of AML patients still face the challenge of disease relapse. In this review, we will explore biomarkers that may predict disease progression in patients receiving venetoclax-based therapy, considering both clinical factors and genetic changes. Despite the many advances, we conclude that the identification of molecular profiles for AML patients who will respond optimally to venetoclax therapy remains an unmet clinical need. Full article
(This article belongs to the Special Issue Advanced Research in Acute Myeloid Leukemia)
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25 pages, 1170 KiB  
Review
The Genetic Landscape of Myelodysplastic Neoplasm Progression to Acute Myeloid Leukemia
by Claudia Bănescu, Florin Tripon and Carmen Muntean
Int. J. Mol. Sci. 2023, 24(6), 5734; https://doi.org/10.3390/ijms24065734 - 17 Mar 2023
Cited by 7 | Viewed by 2990
Abstract
Myelodysplastic neoplasm (MDS) represents a heterogeneous group of myeloid disorders that originate from the hematopoietic stem and progenitor cells that lead to the development of clonal hematopoiesis. MDS was characterized by an increased risk of transformation into acute myeloid leukemia (AML). In recent [...] Read more.
Myelodysplastic neoplasm (MDS) represents a heterogeneous group of myeloid disorders that originate from the hematopoietic stem and progenitor cells that lead to the development of clonal hematopoiesis. MDS was characterized by an increased risk of transformation into acute myeloid leukemia (AML). In recent years, with the aid of next-generation sequencing (NGS), an increasing number of molecular aberrations were discovered, such as recurrent mutations in FLT3, NPM1, DNMT3A, TP53, NRAS, and RUNX1 genes. During MDS progression to leukemia, the order of gene mutation acquisition is not random and is important when considering the prognostic impact. Moreover, the co-occurrence of certain gene mutations is not random; some of the combinations of gene mutations seem to have a high frequency (ASXL1 and U2AF1), while the co-occurrence of mutations in splicing factor genes is rarely observed. Recent progress in the understanding of molecular events has led to MDS transformation into AML and unraveling the genetic signature has paved the way for developing novel targeted and personalized treatments. This article reviews the genetic abnormalities that increase the risk of MDS transformation to AML, and the impact of genetic changes on evolution. Selected therapies for MDS and MDS progression to AML are also discussed. Full article
(This article belongs to the Special Issue Advanced Research in Acute Myeloid Leukemia)
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34 pages, 1997 KiB  
Review
Choosing the Right Cell Line for Acute Myeloid Leukemia (AML) Research
by Rafał Skopek, Małgorzata Palusińska, Katarzyna Kaczor-Keller, Rafał Pingwara, Anna Papierniak-Wyglądała, Tino Schenk, Sławomir Lewicki, Artur Zelent and Łukasz Szymański
Int. J. Mol. Sci. 2023, 24(6), 5377; https://doi.org/10.3390/ijms24065377 - 11 Mar 2023
Cited by 7 | Viewed by 8524
Abstract
Immortalized cell lines are widely used in vitro tools in oncology and hematology research. While these cell lines represent artificial systems and may accumulate genetic aberrations with each passage, they are still considered valuable models for pilot, preliminary, and screening studies. Despite their [...] Read more.
Immortalized cell lines are widely used in vitro tools in oncology and hematology research. While these cell lines represent artificial systems and may accumulate genetic aberrations with each passage, they are still considered valuable models for pilot, preliminary, and screening studies. Despite their limitations, cell lines are cost-effective and provide repeatable and comparable results. Choosing the appropriate cell line for acute myeloid leukemia (AML) research is crucial for obtaining reliable and relevant results. Several factors should be considered when selecting a cell line for AML research, such as specific markers and genetic abnormalities associated with different subtypes of AML. It is also essential to evaluate the karyotype and mutational profile of the cell line, as these can influence the behavior and response to the treatment of the cells. In this review, we evaluate immortalized AML cell lines and discuss the issues surrounding them concerning the revised World Health Organization and the French–American–British classifications. Full article
(This article belongs to the Special Issue Advanced Research in Acute Myeloid Leukemia)
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