Printer Friendly

Navigating through Mutations in Acute Myeloid Leukemia. What Do We Know and What Do We Do with It?


Acute myeloid leukemia (AML) represents a group of diseases that is characterized by the clonal expansion of myeloid blasts in peripheral blood, bone marrow, and other organs and cavities. Acute myeloid leukemia (AML) is reportedly most common in the Western world with the worldwide incidence of 2.5-3 cases per 100,000 population annually (1). A diagnosis of AML can be made based on (1) [greater than or equal to]20% blasts of myeloid and/or monocytic or megakaryocytic lineages and (2) the presence of recurrent cytogenetic abnormalities, including t(8;21) (q22;q22.1), inv16(p13.1q22), or t(16;16) (p13.1:q22) and PML-RARA fusion (1). AML can arise de novo or evolve from myelodysplastic syndromes (MDS) and/or myeloproliferative neoplasms. According to the European LeukemiaNet, the current risk stratification for AML is primarily based on cytogenetics and molecular genetic abnormalities (Table 1) (2). The recent developments in the molecular biology of this clinically, morphologically, and phenotypically heterogeneous disease lead us to a more comprehensive diagnostic approach, including conventional karyotyping, fluorescence in situ hybridization, polymerase chain reaction, and nextgeneration DNA sequencing (NGS) and enable us to predict the prognosis in these patients and develop more effective targeted treatments. NGS is a fairly novel technology that massively parallels or deep sequences the DNA, allowing us to sequence the entire human genome within a day (3). The detection of somatic mutations using NGS in AML cases with large multi-gene panels provides important information that can be used in the diagnosis, prognostic risk stratification, evaluation for targeted treatments, and monitoring for minimal residual disease (MRD).

Mutations in AML and the Clinical Consequences

In AML, the transcription-factor fusions (e.g., t(8;21), inv(16) and t(15;17)) are the first identified genomic alteration and have been linked to disease initiation (4, 5). A recent whole genome sequencing study on 200 adult de novo AML patients published by The Cancer Genome Atlas Research Network classified AMLassociated mutations in functional categories (Table 2) according to the results of this comprehensive analysis (6). The data suggest that one mutation in any of these pathways is sufficient for the pathogenesis of AML and that certain mutations common in AML (e.g., in DNMT3A, NPM1, CEPBA, IDH1/2, and RUNX1) play a role in the initiation of AML similar to the fusion genes.

1n addition to the role in the pathogenesis of AML, these mutations appear to have a clinical utility in the prognostication, determination of the therapy options, and detection of MRD. The recently approved and under investigation agents targeting these mutations are summarized in Table 3.

FLT3 Mutation: Mutations involving the FLT3 gene, a member of the class 11 tyrosine kinase receptor, have been extensively studied and shown to play a crucial role in AML, promoting the expansion of hematopoietic precursors (7). FLT3 is not uncommonly expressed in AML blasts and is associated with poor prognosis. The FLT3 internal tandem duplication (FLT3-ITD) mutations result in an increased tyrosine kinase activity, and they are the first mutations reported to have a prognostic impact in AML (8). Subsequent large cohort studies as well as sporadic case reports have demonstrated the association between FLT3-ITD mutations and an increased relapse rate as well as decreased overall survival (OS) (9-11). Point mutations occurring in the FLT3 gene in the constitutive activation of the kinase domain are known as FLT3-TKD mutations. Both FLT3-ITD and FLT3-TKD mutations occur in AML with a normal karyotype (~35% and 10%, respectively) as well as AML with recurrent cytogenetics (12). The FLT3 mutation analysis was historically performed for prognostication in AML; however, with the advances in FLT3-inhibitors, it now clear that it has a prognostic and predictive value.

NPM1 Mutation: Nucleaophosmin (NPM) is a crucial protein in a wide-spectrum of cell processes, including cell proliferation, DNA repair, and genome stability (13). The frameshift mutations of the NPM1 gene are observed in onethird of adult patients with de novo AML; WHO classifies AML with NPM1 mutation as a separate entity (13). NPM1 mutations are associated with a favorable prognosis in AML with a normal karyotype without other mutations. AML with mutated NPM1 commonly harbors other mutations involving the FLT3 (in 40-50% of patients), DNMT3A, TET2, IDH1, and IDH2 (14) genes. A recent large retrospective study by Ostronoff et al. (15) showed that AML patients aged between 55 and 65 years and with NPM1+/FLT3-ITD+ have an improved survival compared to the group without this phenotype. Mason et al. (14) studied 133 cases with NPM1 mutated AML; 40% of these cases demonstrated an acute promyelocytic leukemia (APL)-like phenotype with lack of CD34 and human leukocyte antigen (HLA)DR expression, suggesting a maturation arrest of myeloid differentiation closer to the promyelocytic stage. Furthermore, these APL-like cases also showed TET2, IDH1, or IDH2 mutations with a superior outcome and lower frequency of DNMT3A mutations. The results of this study were interesting and indicated a potential use of ATRA and ATO in the cases of AML with mutated NPM1 and APL-like phenotype.

CEBPA Mutation: CEBPA, a transcription factor in hematopoietic stem cells, is responsible for the differentiation to the myeloid progenitors and functions as a promoter for myeloid and monocytic differentiation (16). CEBPA is expressed in the granulocytes, monocytes, and eosinophils. CEBPA mutations occur in approximately 10% of AML cases and double mutations confer a favorable diagnosis (16, 17). However, when single mutation of CEBPA occurs, other concurrent mutations, including NPM1 and FLT3-ITD, affect the outcome in these cases (18).

Other mutations that are commonly detected in AML include DN-MT3A, IDH1 and IDH2, RUNX1, ASXL1, TP53, KIT, and TET2.

DNMT3A Mutation: The DNMT genes play a role in the methylation of CpG islands and reduce the expression of downstream genes resulting in genome instability and cancer (19). The DN-MT3A mutations occur in 18-22% of AML cases and onethird of AML cases with normal cytogenetics (20-23). Studies have shown that DNMT3A mutations are often accompanied by other mutations, including FLT3, NPM1, and IDH1 and IDH2 mutations (24) and confer an unfavorable prognosis in both younger and older patients (17). Treatment with high dose daunorubicin (25) and hematopoietic stem cell transplant (19) have shown to increase the OS in AML patients with DNMT3A mutation.

IDH1 and IDH2 Mutation: IDH is an essential enzyme in cell metabolism, and gain of function mutations in IDH leads to DNA methylation and impaired myeloid differentiation (26). Approximately 20% of all AML and 30% of AML with normal karyotype cases harbor IDH1 or IDH2 mutations (27). IDH1 mutations are shown to confer an overall unfavorable prognosis in AML with shorter OS and event-free survival, while the impact of IDH2 mutations differs based on the type of mutation: [IDH2.sup.R140] are associated with a better prognosis in younger AML patients, whereas [IDH2.sup.R172] is associated with a poorer outcome (28, 29). IDH1/IDH2 small inhibitor molecules are available in the treatment of AML.

RUNX1 Mutation: AML with RUNX1 is a relatively infrequent provisional AML entity. The RUNX1 mutation frequency increased with age: 5-10% in patients aged <60 years and 10-20% in those aged [greater than or equal to]60 years. It is more frequent in men than in women and is often associated with secondary AML evolving from MDS, failure of induction therapy, and inferior OS (30).

ASXL1 Mutation: The ASXL1 mutations are detected in approximately 10% of all de novo AML cases, and the frequency increases significantly with age, particularly in patients aged >60 years. The ASXL1 mutation in AML is associated with an inferior outcome with low complete remission rates.

TP53 Mutation: The p53 protein is a tumor suppressor transcription factor that is actively involved in hematopoietic stem cell quiescence and self-renewal, preventing leukemogenesis (31). The TP53 mutations in AML have recently been the focus of investigations. They occur in 8% of de novo AML and are early leukemogenic initiating driver mutations, resulting in an aggressive disease course, therapy-resistance, and poor outcome even after allogeneic HSCT (32). MDM2 inhibitors appear to be promising in targeting mutant p53 in AML treatment, although the therapeutic progress is still inadequate.

KIT Mutation: The KIT mutation is found in 13-46% of the core-binding protein factor (CBF) AML, including t(8;21)(q22;q22) and inv(16)(p13;q22) (33). While CBF-AML is generally considered in the favorable risk group, the co-existence of KIT mutation is associated with unfavorable prognosis. Targeted tyrosine kinase inhibition of KIT is still in development.

TET2 Mutation: The somatic methylcytosine dioxygenase "ten-eleven translocation 2" (TET2) mutations occur in approximately 23% of AML cases (34). The TET2 mutation is a common finding among the elderly population with clonal hematopoiesis. It is often associated with AML of the normal karyotype and NPM1 mutation (30).


Acute myeloid leukemia (AML) is the most common acute leukemia condition in the adult population, which has a complex biology and significant heterogeneity. Over the last few decades, many balanced and unbalanced chromosomal abnormalities and mutations have been described that are used to diagnose as well as prognosticate the disease. Despite the advances in molecular pathogenesis and targeted drug discoveries, the overall longterm survival in a majority of the patients remains poor. The treatment of AML using conventional therapies is challenging owing to the advanced age of onset and exclusion of optimal cytotoxic treatments in the elderly patient group due to increased complications and decreased tolerance. Several targeted therapies, such as FLT3-inhibitors, have been introduced for AML. However, the single-targeted-therapy option less likely to succeed due to the molecular heterogeneity of the disease and co-existing mutations and translocations. Further understanding of the complex biology of AML and identification of the optimal targeted treatments will particularly benefit patients of older age as well as those with a complex karyotype and refractory disease.

Peer-review: Externally peer-reviewed.

Conflict of Interest: The author has no conflicts of interest to declare.

Financial Disclosure: The author declared that this study has received no financial support.


(1.) Swerdlow SH, World Health Organization, International Agency for Research on Cancer. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th edition. ed. Lyon: 1nternational Agency for Research on Cancer 2017; pages 585.

(2.) Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115(3): 453-74.

(3.) Behjati S, Tarpey PS. What is next generation sequencing? Arch Dis Child Educ Pract Ed 2013; 98(6): 236-8.

(4.) Rowley JD. Chromosomal translocations: revisited yet again. Blood 2008; 112(6): 2183-9.

(5.) Mrozek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev 2004; 18(2): 115-36.

(6.) Cancer Genome Atlas Research N, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368(22): 2059-74.

(7.) Lyman SD, Jacobsen SE. c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 1998; 91(4): 1101-34.

(8.) Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 1999; 93(9): 3074-80.

(9.) Kottaridis PD, Gale RE, Langabeer SE, Frew ME, Bowen DT, Linch DC. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood 2002; 100(7): 2393-8.

(10.) Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002; 100(13): 4372-80.

(11.) Pratz KW, Levis M. How 1 treat FLT3-mutated AML. Blood 2017; 129(5): 565-71.

(12.) Patnaik MM. The importance of FLT3 mutational analysis in acute myeloid leukemia. Leuk Lymphoma 2017: 1-14.

(13.) Handschuh L, Wojciechowski P, Kazmierczak M, Marcinkowska-Swojak M, Luczak M, Lewandowski K, et al. NPM1 alternative transcripts are upregulated in acute myeloid and lymphoblastic leukemia and their expression level affects patient outcome. J Transl Med 2018; 16(1): 232.

(14.) Mason EF, Kuo FC, Hasserjian RP, Seegmiller AC, Pozdnyakova O. A distinct immunophenotype identifies a subset of NPM1-mutated AML with TET2 or IDH1/2 mutations and improved outcome. Am J Hematol 2018; 93(4): 504-10.

(15.) Ostronoff F, Othus M, Lazenby M, Estey E, Appelbaum FR, Evans A, et al. Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research 1nstitute/Medical Research Council report. J Clin Oncol 2015; 33(10): 1157-64.

(16.) Song G, Wang L, Bi K, Jiang G. Regulation of the C/EBPalpha signaling pathway in acute myeloid leukemia (Review). Oncol Rep 2015; 33(5): 2099-106.

(17.) Dohner K, Paschka P. 1ntermediate-risk acute myeloid leukemia therapy: current and future. Hematology Am Soc Hematol Educ Program 2014; 2014(1): 34-43.

(18.) Taskesen E, Bullinger L, Corbacioglu A, Sanders MA, Erpelinck CA, Wouters BJ, et al. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood 2011; 117(8): 2469-75.

(19.) Yang X, Shi J, Zhang X, Zhang G, Zhang J, Yang S, et al. Biological and clinical influences of NPM1 in acute myeloid leukemia patients with DNMT3A mutations. Cancer Manag Res 2018; 10: 2489-97.

(20.) Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363(25): 2424-33.

(21.) Thol F, Damm F, Ludeking A, Winschel C, Wagner K, Morgan M, et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol 2011; 29(21): 2889-96.

(22.) Gaidzik VI, Schlenk RF, Paschka P, Stolzle A, Spath D, Kuendgen A, et al. Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG). Blood 2013; 121(23): 4769-77.

(23.) Marcucci G, Metzeler KH, Schwind S, Becker H, Maharry K, Mrozek K, 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(7): 742-50.

(24.) Yohe S. Molecular Genetic Markers in Acute Myeloid Leukemia. J Clin Med 2015; 4(3): 460-78.

(25.) Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366(12): 1079-89.

(26.) Zhang X, Shi J, Zhang J, Yang X, Zhang G, Yang S, et al. Clinical and biological implications of IDH1/2 in acute myeloid leukemia with [DNMT3A.sup.mut]. Cancer Manag Res 2018; 10: 2457-66.

(27.) Marcucci G, Haferlach T, Dohner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol 2011; 29(5): 475-86.

(28.) Rakheja D, Konoplev S, Medeiros LJ, Chen W. 1DH mutations in acute myeloid leukemia. Hum Pathol 2012; 43(10): 1541-51.

(29.) Xu Q, Li Y, Lv N, Jing Y, Xu Y, Li Y, et al. Correlation Between Isocitrate Dehydrogenase Gene Aberrations and Prognosis of Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis. Clin Cancer Res 2017; 23(15): 4511-22.

(30.) Bullinger L, Dohner K, Dohner H. Genomics of Acute Myeloid Leukemia Diagnosis and Pathways. J Clin Oncol 2017; 35(9): 934-46.

(31.) Pant V, Quintas-Cardama A, Lozano G. The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans. Blood 2012; 120(26): 5118-27.

(32.) 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(6): 699-712.

(33.) Ayatollahi H, Shajiei A, Sadeghian MH, Sheikhi M, Yazdandoust E, Ghazanfarpour M, et al. Prognostic Importance of C-KIT Mutations in Core Binding Factor Acute Myeloid Leukemia: A Systematic Review. Hematol Oncol Stem Cell Ther 2017; 10(1): 1-7.

(34.) Shih AH, Abdel-Wahab O, Patel JP, Levine RL. The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer 2012; 12(9): 599-612.

Cite this article as:

Peker D. Navigating through Mutations in Acute Myeloid Leukemia. What Do We Know and What Do We Do with It? Erciyes Med J 2018; 40(4): 183-7.

Comprehensive Cancer Center and Department of Pathology The University of Alabama at Birmingham, AL, USA





Available Online Date



Deniz Peker, Comprehensive Cancer Center and Department of Pathology, The University of Alabama at Birmingham, AL, USA


DOI: 10.5152/etd.2018.18136
Table 1. Risk stratification for AML according to the European
LeukemiaNet (2)

Genetic Group    Subsets

Favorable        t(8;21)(q22;q22); RUNX1-RUNX1T1
                 inv(16)(p13.1q22) or t(16;16)
                 (p13.1;q22); CBFB-MYH11
                 Mutated NPM1 without FLT3-ITD
                 (normal karyotype)
                 Mutated CEBPA (normal karyotype)
Intermediate-I   Mutated NPM1 and FLT3-ITD
                 (normal karyotype)
                 Wild-type NPM1 and FLT3-ITD
                 (normal karyotype)
                 Wild-type NPM1 without FLT3-ITD
                 (normal karyotype)
Intermediate-II  t(9;11)(p22;q23); MLLT3-MLL
                 Cytogenetic abnormalities not
                 classified as favorable or adverse
Adverse          inv(3)(q21q26.2) or t(3;3)
                 (q21;q26.2); RPN1-EVI1
                 t(6;9)(p23;q34); DEK-NUP214
                 t(v;11)(v;q23); MLL rearranged
                 -5 or del(5q); -7; abnl(17p);
                 complex karyotype (*)

(*) Complex karyotype is defined by three or more chromosome
abnormalities in the absence of designated recurrent translocations or
inversions by tWHO.

Table 2. Functional gene groups in AML according to the cancer genome
atlas research network (6)

Functional Gene Group       Genes in the Group

Spliceosome                 CSTF2T, DDX1, DDX23,
                            DHX32, HNRNPK, METTL3,
                            PLRG1, PRPF3, PRPF8, RBMX,
                            F3B1, SNRNP200, SRRM2,
                            SRSF6, SUPT5H, TRA2B,
                            U2AF1, U2AF1L4, U2AF2
Cohesin complex             SMC1A, SMC3, SMC5, STAG2,
MLL-X fusions               MLL-ELL, MLL-MLLT4, MLL-
                            MLLT3, MLLT10-MLL
RAS protein                 KRAS, NRAS
Other epigenetic modifiers  ARID4B, ASXL2, ASXL3,
                            BRPF1, CBX5, CBX7, EED,
                            HDAC2, HDAC3, JMJD1C,
                            KAT6B, KDM2B, KDM3B,
                            MLL2, MLL3, MTA2, PRDM9,
                            PRDM16, RBBP4, SAP130,
                            SCML2, SUDS3, SUZ12,
                            ZBTB33, ZBTB7B,
                            RPN1-MECOM, RUNX1-
Other tyrosine kinase       ABL1, DYRK4, EPHA2,
                            EPHA3, JAK3, MST1R,
                            OBSCN, PDGFRB, WEE1
Serine/threonine kinase     ACVR2B, ADRBK1, AKAP13,
                            BUB1, CPNE3, DCLK1,
                            MAPK1, YLK2, MYO3A, NRK,
                            PRKCG, RPS6KA6, SMG1,
                            STK32A, STK33, STK36, TRIO,
                            TTBK1, WNK3, WNK4
Protein tyrosine            PTPN11, PTPRT, PTPN14
Other myeloid               GATA2, CBFB, ETV6, ETV3,
transcription factors       GLI1, IKZF1, MYB, MYC,

Table 3. Targeted treatments for AML, FDA-approved and under
investigation agents

Target  Drug(s)                 Approval status (*)  Indication

FLT3    Crenolanib              Approved             New dx AML with
                                                     FLT3 mutation
IDH2    Enasidenib              Approved             Adults with
                                                     relapsed or
                                                     refractory AML
                                                     associated with
                                                     IDH2 mutations.
IDH1    Ivosidenib              Approved             Adults with
                                                     relapsed or
                                                     refractory AML
                                                     associated with
                                                     IDH1 mutation
        FT-2102 and others      Investigational
BCL2    Venetoclax              Investigational
TET2    Vitamin C and           Approved (*)         AML with low blast
                                                     count (*)
        hypomethylating agents
CD33    Gemtuzumab ozogamicin   Approved             Newly diagnosed
                                                     CD33-positive AML
MDM2    Idasanutlin             Investigational

(*) US Food and Drug Administration (FDA) approval status
(#) Hypomethylating agent (azacitidine) approved for low blast count
AML in the US
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2018 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Peker, Deniz
Publication:Erciyes Medical Journal
Date:Dec 1, 2018
Previous Article:Community-Acquired Pneumonia in Adults: What's New Focusing on Epidemiology, Microorganisms and Diagnosis?
Next Article:Functions of the Human Intestinal Microbiota in Relation to Functional Foods.

Terms of use | Privacy policy | Copyright © 2022 Farlex, Inc. | Feedback | For webmasters |