A concise review on the molecular genetics of acute myeloid leukemia

Padmakumar, Devipriya; Chandraprabha, Vineetha Radhakrishnan; Gopinath, Preethi; Devi, Akhila Raj Thampirajan Vimala; Anitha, Geetha Raj John; Sreelatha, Mahitha Mohanan; Padmakumar, Amritha; Subramanian, Hariharan

doi:10.1016/j.leukres.2021.106727

Cited by 51 publications

(49 citation statements)

References 91 publications

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“…Indeed, the FLT3-ITD mutations predict a worse prognosis for patients through the activation of several oncogenic pathways (e.g., RAS/MAPK, STAT5, and PI3K/AKT) [ 11 ]. On the other hand, mutations that affect NPM1 are favorable in terms of OS and disease-free survival (DFS) and are associated with lower incidence of relapse [ 2 ]. However, when co-occurring, these two genetic alterations determine a high risk of a worse clinical course for patients, underlying the crucial role of these genes in AML development and progression.…”

Section: Discussionmentioning

confidence: 99%

“…Acute myeloid leukemia (AML) is an extremely heterogeneous hematologic malignancy, characterized by clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues [ 1 ]. This malignancy comprises most acute leukemias cases affecting the myeloid lineage and accounts for about 20% of all acute leukemias in children and 80% in adults [ 2 , 3 , 4 ]. In Europe, the incidence of AML is approximately 3.7 per 100,000 persons/year [ 5 ], among which 2–3% of cases are pediatric [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…AML is a highly complex disease characterized by a plethora of cytogenetic alterations and genetic mutations, which are used to classify AML. Figure 1 shows the frequencies of the most relevant mutations described for AML, which affect the following genes: Fms-Like Tyrosine Kinase 3 (FLT3) [ 11 ], KIT [ 12 ], RAS [ 13 ], Nucleophosmin 1 (NPM1) [ 14 ], CCAAT Enhancer Binding Protein α (CEBPA) [ 2 ], Runt-related transcription factor (RUNX1) [ 12 ], DNA methyltransferase 3A (DNMT3A) [ 15 ], Isocitrate dehydrogenase (IDH) [ 12 ], Ten–eleven translocation 2 (TET2) [ 2 ], Additional sex comb-like 1 (ASXL1) [ 2 ], Wilms’ tumor 1 (WT1) [ 12 ], and Tumor protein 53 (TP53) [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

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2-Hydroxyglutarate in Acute Myeloid Leukemia: A Journey from Pathogenesis to Therapies

et al. 2022

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The oncometabolite 2-hydroxyglutarate (2-HG) plays a key role in differentiation blockade and metabolic reprogramming of cancer cells. Approximatively 20–30% of acute myeloid leukemia (AML) cases carry mutations in the isocitrate dehydrogenase (IDH) enzymes, leading to a reduction in the Krebs cycle intermediate α-ketoglutarate (α-KG) to 2-HG. Relapse and chemoresistance of AML blasts following initial good response to standard therapy account for the very poor outcome of this pathology, which represents a great challenge for hematologists. The decrease of 2-HG levels through pharmacological inhibition of mutated IDH enzymes induces the differentiation of AML blasts and sensitizes leukemic cells to several anticancer drugs. In this review, we provide an overview of the main genetic mutations in AML, with a focus on IDH mutants and the role of 2-HG in AML pathogenesis. Moreover, we discuss the impact of high levels of 2-HG on the response of AML cells to antileukemic therapies and recent evidence for highly efficient combinations of mutant IDH inhibitors with other drugs for the management of relapsed/refractory (R/R) AML.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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2-Hydroxyglutarate in Acute Myeloid Leukemia: A Journey from Pathogenesis to Therapies

et al. 2022

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“…The WT1 transcript was detected in 80–86% of ALL patients and in 93% of AML patients. In contrast to acute leukemia, mononuclear cells from bone marrow or peripheral blood of healthy volunteers did not express the WT1 gene at detectable levels ( Menssen et al, 1995 ; Padmakumar et al, 2021 ). Mutations in exons 7 and 9 of WT1 have been identified in acute myeloid leukemia and are related to poorer prognosis and resistance to treatment ( Aref et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic and Epigenetic Signatures in Acute Promyelocytic Leukemia Treatment and Molecular Remission

et al. 2022

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Acute myeloid leukemia (AML) is an aggressive, heterogeneous group of malignancies with different clinical behaviors and different responses to therapy. For many types of cancer, finding cancer early makes it easier to treat. Identifying prognostic molecular markers and understanding their biology are the first steps toward developing novel diagnostic tools or therapies for patients with AML. In this study, we defined proteins and genes that can be used in the prognosis of different acute leukemia cases and found possible uses in diagnostics and therapy. We analyzed newly diagnosed acute leukemia cases positive for t (15; 17) (q22; q21) PML-RAR alpha, acute promyelocytic leukemia (APL). The samples of bone marrow cells were collected from patients at the diagnosis stage, as follow-up samples during standard treatment with all-trans retinoic acid, idarubicin, and mitoxantrone, and at the molecular remission. We determined changes in the expression of genes involved in leukemia cell growth, apoptosis, and differentiation. We observed that WT1, CALR, CAV1, and MYC genes’ expression in all APL patients with no relapse history was downregulated after treatment and could be potential markers associated with the pathology, thereby revealing the potential value of this approach for a better characterization of the prediction of APL outcomes.

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“…Acute myeloid leukemia (AML) is a complex disorder of the bone marrow (BM) that results from the aberrant clonal expansion of myeloid progenitors that have acquired genomic aberrations and mutations, which provide a growth advantage and a block of differentiation [ 81 ]. In addition, miRNAs are aberrantly expressed in all subtypes of AML [ 82 , 83 , 84 ].…”

Section: Mir139 Expression Is Repressed In Various Types Of ...mentioning

confidence: 99%

MicroRNA-139, an Emerging Gate-Keeper in Various Types of Cancer

Stavast

Zuijen

Erkeland

2022

Cells

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Mounting data show that MIR139 is commonly silenced in solid cancer and hematological malignancies. MIR139 acts as a critical tumor suppressor by tuning the cellular response to different types of stress, including DNA damage, and by repressing oncogenic signaling pathways. Recently, novel insights into the mechanism of MIR139 silencing in tumor cells have been described. These include epigenetic silencing, inhibition of POL-II transcriptional activity on gene regulatory elements, enhanced expression of competing RNAs and post-transcriptional regulation by the microprocessor complex. Some of these MIR139-silencing mechanisms have been demonstrated in different types of cancer, suggesting that these are more general oncogenic events. Reactivation of MIR139 expression in tumor cells causes inhibition of tumor cell expansion and induction of cell death by the repression of oncogenic mRNA targets. In this review, we discuss the different aspects of MIR139 as a tumor suppressor gene and give an overview on different transcriptional mechanisms regulating MIR139 in oncogenic stress and across different types of cancer. The novel insights into the expression regulation and the tumor-suppressing activities of MIR139 may pave the way to new treatment options for cancer.

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A concise review on the molecular genetics of acute myeloid leukemia

Cited by 51 publications

References 91 publications

2-Hydroxyglutarate in Acute Myeloid Leukemia: A Journey from Pathogenesis to Therapies

2-Hydroxyglutarate in Acute Myeloid Leukemia: A Journey from Pathogenesis to Therapies

Genetic and Epigenetic Signatures in Acute Promyelocytic Leukemia Treatment and Molecular Remission

MicroRNA-139, an Emerging Gate-Keeper in Various Types of Cancer

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