Role of Gene Mutations in Acute Myeloid Leukemia: A Review Article

Abstract

Acute myeloid leukemia (AML) is an immensely heterogeneous disease characterized by the clonal growth of promyelocytes or myeloblasts in bone marrow as well as in peripheral blood or tissue.
Enhancement in the knowledge of the molecular biology of cancer and recognition of intermittent mutations in AML contribute to favorable circumstances to establish targeted therapies and enhance the clinical outcome. There is high interest in the development of therapies that target definitive abnormalities in AML while eradicating leukemia-initiating cells. In recent years, there has been a better knowledge of the molecular abnormalities that lead to the progression of AML, and the application of new methods in molecular biology techniques has increased that facilitating the advancement of investigational drugs.
In this review, literature or information on various gene mutations for AML is discussed. English language articles were scrutinized in plentiful directories or databases like PubMed, Science Direct, Web of Sciences, Google Scholar, and Scopus. The important keywords used for searching databases is “Acute myeloid leukemia”, “Gene mutation in Acute myeloid leukemia”, “Genetic alteration in Acute myeloid leukemia,” and “Genetic abnormalities in Acute myeloid leukemia.”

Keywords

Acute myeloid leukemia / gene mutation / genetic alteration

References

[1] Chen J, Odenike O, Rowley JD.Leukaemogenesis: more than mutant genes. Nat Rev Cancer 2010; 10(01) 23-36

[2] Döhner H, Estey E, Grimwade D.et al.Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 129(04) 424-447

[3] Ediriwickrema A, Gentles AJ, Majeti R.Single-cell genomics in AML: extending the frontiers of AML research. Blood 2023; 141(04) 345-355

[4] McGrattan P, Humphreys M, Hull D, McMullin MF. Transformation of cytogenetically normal chronic myelomonocytic leukaemia to an acute myeloid leukaemia and the emergence of a novel +13, +15 double trisomy resulting in an adverse outcome. Ulster Med J 2007; 76(03) 131-135

[5] Thomas D, Majeti R.Biology and relevance of human acute myeloid leukemia stem cells. Blood 2017; 129(12) 1577-1585

[6] Döhner H, Wei AH, Appelbaum FR.et al.Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022; 140(12) 1345-1377

[7] Wang Y, Xiao M, Chen X.et al.WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation. Mol Cell 2015; 57(04) 662-673

[8] Paschka P, Marcucci G, Ruppert AS.et al.Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 2008; 26(28) 4595-4602

[9] Virappane P, Gale R, Hills R.et al.Mutation of the Wilms' tumor 1 gene is a poor prognostic factor associated with chemotherapy resistance in normal karyotype acute myeloid leukemia: the United Kingdom Medical Research Council Adult Leukaemia Working Party. J Clin Oncol 2008; 26(33) 5429-5435

[10] Krauth MT, Alpermann T, Bacher U.et al.WT1 mutations are secondary events in AML, show varying frequencies and impact on prognosis between genetic subgroups. Leukemia 2015; 29(03) 660-667

[11] Haferlach C, Dicker F, Herholz H, Schnittger S, Kern W, Haferlach T.Mutations of the TP53 gene in acute myeloid leukemia are strongly associated with a complex aberrant karyotype. Leukemia 2008; 22(08) 1539-1541

[12] Prokocimer M, Molchadsky A, Rotter V.Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy. Blood 2017; 130(06) 699-712

[13] Rücker FG, Schlenk RF, Bullinger L.et al.TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood 2012; 119(09) 2114-2121

[14] Metzeler KH, Maharry K, Radmacher MD.et al.TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2011; 29(10) 1373-1381

[15] Delhommeau F, Dupont S, Della Valle V.et al.Mutation in TET2 in myeloid cancers. N Engl J Med 2009; 360(22) 2289-2301

[16] Weissmann S, Alpermann T, Grossmann V.et al.Landscape of TET2 mutations in acute myeloid leukemia. Leukemia 2012; 26(05) 934-942

[17] Abdel-Wahab O, Mullally A, Hedvat C.et al.Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009; 114(01) 144-147

[18] Figueroa ME, Abdel-Wahab O, Lu C.et al.Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010; 18(06) 553-567

[19] Shih AH, Abdel-Wahab O, Patel JP, Levine RL.The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer 2012; 12(09) 599-612

[20] Krivtsov AV, Armstrong SA.MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 2007; 7(11) 823-833

[21] Ernst P, Wang J, Korsmeyer SJ.The role of MLL in hematopoiesis and leukemia. Curr Opin Hematol 2002; 9(04) 282-287

[22] Huret JL, Dessen P, Bernheim A.An atlas of chromosomes in hematological malignancies. Example: 11q23 and MLL partners. Leukemia 2001; 15(06) 987-989

[23] Meyer C, Kowarz E, Hofmann J.et al.New insights to the MLL recombinome of acute leukemias. Leukemia 2009; 23(08) 1490-1499

[24] Abdel-Wahab O, Gao J, Adli M.et al.Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J Exp Med 2013; 210(12) 2641-2659

[25] Abdel-Wahab O, Adli M, LaFave LM.et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell 2012; 22(02) 180-193

[26] Metzeler KH, Becker H, Maharry K.et al.ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category. Blood 2011; 118(26) 6920-6929

[27] Gelsi-Boyer V, Trouplin V, Adélaïde J.et al.Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol 2009; 145(06) 788-800

[28] Carbuccia N, Trouplin V, Gelsi-Boyer V.et al.Mutual exclusion of ASXL1 and NPM1 mutations in a series of acute myeloid leukemias. Leukemia 2010; 24(02) 469-473

[29] Liang DC, Liu HC, Yang CP.et al.Cooperating gene mutations in childhood acute myeloid leukemia with special reference on mutations of ASXL1, TET2, IDH1, IDH2, and DNMT3A. Blood 2013; 121(15) 2988-2995

[30] Asada S, Goyama S, Inoue D.et al.Mutant ASXL1 cooperates with BAP1 to promote myeloid leukaemogenesis. Nat Commun 2018; 9(01) 2733

[31] Yan XJ, Xu J, Gu ZH.et al.Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 2011; 43(04) 309-315

[32] Thol F, Damm F, Lüdeking A.et al.Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol 2011; 29(21) 2889-2896

[33] Ley TJ, Ding L, Walter MJ.et al.DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363(25) 2424-2433

[34] Marcucci G, Metzeler KH, Schwind S.et al.Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol 2012; 30(07) 742-750

[35] Sehgal AR, Gimotty PA, Zhao J.et al.DNMT3A Mutational status affects the results of dose-escalated induction therapy in acute myelogenous leukemia. Clin Cancer Res 2015; 21(07) 1614-1620

[36] Ball B, Zeidan A, Gore SD, Prebet T.Hypomethylating agent combination strategies in myelodysplastic syndromes: hopes and shortcomings. Leuk Lymphoma 2017; 58(05) 1022-1036

[37] Metzeler KH, Walker A, Geyer S.et al.DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. Leukemia 2012; 26(05) 1106-1107

[38] Cashen AF, Schiller GJ, O'Donnell MR, DiPersio JF. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol 2010; 28(04) 556-561

[39] Issa JJ, Roboz G, Rizzieri D.et al.Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol 2015; 16(09) 1099-1110

[40] Losman JA, Looper RE, Koivunen P.et al.(R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 2013; 339(6127): 1621-1625

[41] Ward PS, Patel J, Wise DR.et al.The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010; 17(03) 225-234

[42] Ernst T, Chase AJ, Score J.et al.Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nat Genet 2010; 42(08) 722-726

[43] Chase A, Cross NC.Aberrations of EZH2 in cancer. Clin Cancer Res 2011; 17(09) 2613-2618

[44] Herviou L, Cavalli G, Cartron G, Klein B, Moreaux J.EZH2 in normal hematopoiesis and hematological malignancies. Oncotarget 2016; 7(03) 2284-2296

[45] Xu B, On DM, Ma A.et al.Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood 2015; 125(02) 346-357

[46] Fujita S, Honma D, Adachi N.et al.Dual inhibition of EZH1/2 breaks the quiescence of leukemia stem cells in acute myeloid leukemia. Leukemia 2018; 32(04) 855-864

[47] Thiede C, Koch S, Creutzig E.et al.Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 2006; 107(10) 4011-4020

[48] Schnittger S, Schoch C, Kern W.et al.Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 2005; 106(12) 3733-3739

[49] Falini B, Nicoletti I, Martelli MF, Mecucci C.Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood 2007; 109(03) 874-885

[50] Falini B, Bolli N, Shan J.et al.Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML. Blood 2006; 107(11) 4514-4523

[51] Döhner K, Schlenk RF, Habdank M.et al.Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 2005; 106(12) 3740-3746

[52] Mrózek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD.Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification?. Blood 2007; 109(02) 431-448

[53] Wang CQ, Krishnan V, Tay LS.et al.Disruption of Runx1 and Runx3 leads to bone marrow failure and leukemia predisposition due to transcriptional and DNA repair defects. Cell Rep 2014; 8(03) 767-782

[54] Chakraborty S, Njah K, Pobbati AV.et al.Agrin as a mechanotransduction signal regulating YAP through the hippo pathway. Cell Rep 2017; 18(10) 2464-2479

[55] Tang JL, Hou HA, Chen CY.et al.AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood 2009; 114(26) 5352-5361

[56] Marcucci G, Haferlach T, Döhner H.Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol 2011; 29(05) 475-486

[57] Mendler JH, Maharry K, Radmacher MD.et al.RUNX1 mutations are associated with poor outcome in younger and older patients with cytogenetically normal acute myeloid leukemia and with distinct gene and MicroRNA expression signatures. J Clin Oncol 2012; 30(25) 3109-3118

[58] Gaidzik VI, Bullinger L, Schlenk RF.et al.RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group. J Clin Oncol 2011; 29(10) 1364-1372

[59] Haferlach T, Stengel A, Eckstein S.et al.The new provisional WHO entity 'RUNX1 mutated AML' shows specific genetics but no prognostic influence of dysplasia. Leukemia 2016; 30(10) 2109-2112

[60] Simon L, Lavallée VP, Bordeleau ME.et al.Chemogenomic landscape of RUNX1-mutated AML reveals importance of RUNX1 allele dosage in genetics and glucocorticoid sensitivity. Clin Cancer Res 2017; 23(22) 6969-6981

[61] Döhner H, Weisdorf DJ, Bloomfield CD.Acute myeloid leukemia. N Engl J Med 2015; 373(12) 1136-1152

[62] Schlenk RF, Döhner K, Krauter J.et al; German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358(18) 1909-1918

[63] Wouters BJ, Löwenberg B, Erpelinck-Verschueren CA, van Putten WL, Valk PJ, Delwel R. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood 2009; 113(13) 3088-3091

[64] Pulikkan JA, Tenen DG, Behre G.C/EBPα deregulation as a paradigm for leukemogenesis. Leukemia 2017; 31(11) 2279-2285

[65] Green CL, Koo KK, Hills RK, Burnett AK, Linch DC, Gale RE.Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol 2010; 28(16) 2739-2747

[66] Gilliland DG, Griffin JD.The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 100(05) 1532-1542

[67] Grafone T, Palmisano M, Nicci C, Storti S.An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment. Oncol Rev 2012; 6(01) e8

[68] Nakao M, Yokota S, Iwai T.et al.Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 1996; 10(12) 1911-1918

[69] Yamamoto Y, Kiyoi H, Nakano Y.et al.Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97(08) 2434-2439

[70] O'Donnell MR, Tallman MS, Abboud CN.et al. Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2017; 15(07) 926-957

[71] Nagel G, Weber D, Fromm E.et al; German-Austrian AML Study Group (AMLSG). Epidemiological, genetic, and clinical characterization by age of newly diagnosed acute myeloid leukemia based on an academic population-based registry study (AMLSG BiO). Ann Hematol 2017; 96(12) 1993-2003

[72] Dhillon S.Gilteritinib: first global approval. Drugs 2019; 79(03) 331-339

[73] Mendel DB, Laird AD, Xin X.et al.In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003; 9(01) 327-337

[74] O'Farrell AM, Abrams TJ, Yuen HA.et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003; 101(09) 3597-3605

[75] O'Farrell AM, Foran JM, Fiedler W.et al. An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res 2003; 9(15) 5465-5476

[76] Teng CL, Yu CT, Hwang WL.et al.Effector mechanisms of sunitinib-induced G1 cell cycle arrest, differentiation, and apoptosis in human acute myeloid leukaemia HL60 and KG-1 cells. Ann Hematol 2013; 92(03) 301-313

[77] Yee KW, Schittenhelm M, O'Farrell AM. et al. Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells. Blood 2004; 104(13) 4202-4209

[78] Zhang H, Savage S, Schultz AR.et al.Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms. Nat Commun 2019; 10(01) 244

[79] Sandmaier BM, Khaled S, Oran B, Gammon G, Trone D, Frankfurt O.Results of a phase 1 study of quizartinib as maintenance therapy in subjects with acute myeloid leukemia in remission following allogeneic hematopoietic stem cell transplant. Am J Hematol 2018; 93(02) 222-231

[80] Altman JK, Foran JM, Pratz KW, Trone D, Cortes JE, Tallman MS.Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Am J Hematol 2018; 93(02) 213-221

[81] Röllig C, Serve H, Hüttmann A.et al; Study Alliance Leukaemia. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol 2015; 16(16) 1691-1699

[82] Zhang C, Lam SSY, Leung GMK.et al.Sorafenib and omacetaxine mepesuccinate as a safe and effective treatment for acute myeloid leukemia carrying internal tandem duplication of Fms-like tyrosine kinase 3. Cancer 2020; 126(02) 344-353

[83] Sasaki K, Kantarjian HM, Kadia T.et al.Sorafenib plus intensive chemotherapy improves survival in patients with newly diagnosed, FLT3-internal tandem duplication mutation-positive acute myeloid leukemia. Cancer 2019; 125(21) 3755-3766

[84] Sattler M, Salgia R.Targeting c-Kit mutations: basic science to novel therapies. Leuk Res 2004; 28(Suppl. 01) S11-S20

[85] Jung CL, Kim HJ, Kim DH, Huh H, Song MJ, Kim SH.CKIT mutation in therapy-related acute myeloid leukemia with MLLT3/MLL chimeric transcript from t(9;11)(p22;q23). Ann Clin Lab Sci 2011; 41(02) 193-196

[86] Marcucci G, Mrózek K, Ruppert AS.et al.Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. J Clin Oncol 2005; 23(24) 5705-5717

[87] Paschka P, Marcucci G, Ruppert AS.et al; Cancer and Leukemia Group B. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol 2006; 24(24) 3904-3911

[88] Welch JS, Ley TJ, Link DC.et al.The origin and evolution of mutations in acute myeloid leukemia. Cell 2012; 150(02) 264-278

[89] Kon A, Shih LY, Minamino M.et al.Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. Nat Genet 2013; 45(10) 1232-1237

RIGHTS & PERMISSIONS

2023 Global Medical Genetics