Updates in molecular genetics of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a type of cancer caused by aggressive neoplastic proliferations of immature myeloid cells that is fatal if untreated. AML accounts for 1.0% of all new cancer cases in the United States, with a 5-year relative survival rate of 30.5%. Once defined primarily morphologically, advances in next generational sequencing have expanded the role of molecular genetics in categorizing the disease. As such, both the World Health Organization Classification of Haematopoietic Neoplasms and The International Consensus Classification System now define a variety of AML subsets based on mutations in driver genes such as NPM1, CEBPA, TP53, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2. This article provides an overview of some of the genetic mutations associated with AML and compares how the new classification systems incorporate molecular genetics into the definition of AML.

[1]  G. Garcia-Manero,et al.  Consensus proposal for revised International Working Group response criteria for higher risk myelodysplastic syndromes. , 2023, Blood.

[2]  A. Porwit,et al.  The International Consensus Classification of acute myeloid leukemia , 2022, Virchows Archiv.

[3]  B. Ebert,et al.  Diagnosis and Management of AML in Adults: 2022 ELN Recommendations from an International Expert Panel. , 2022, Blood.

[4]  M. Loh,et al.  International Consensus Classification of Myeloid Neoplasms and Acute Leukemia: Integrating Morphological, Clinical, and Genomic Data. , 2022, Blood.

[5]  Y. Natkunam,et al.  The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms , 2022, Leukemia.

[6]  T. McDonnell,et al.  Pure erythroid leukemia is characterized by biallelic TP53 inactivation and abnormal p53 expression patterns in de novo and secondary cases , 2022, Haematologica.

[7]  M. Jongen‐Lavrencic,et al.  Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome , 2022, Blood.

[8]  Long Su,et al.  Acute Myeloid Leukemia With CEBPA Mutations: Current Progress and Future Directions , 2022, Frontiers in Oncology.

[9]  P. D. Dal Cin,et al.  TP53 mutation defines a unique subgroup within complex karyotype de novo and therapy-related MDS/AML , 2022, Blood advances.

[10]  Dao-bin Zhou,et al.  Distinct Mutation Landscapes Between Acute Myeloid Leukemia With Myelodysplasia-Related Changes and De Novo Acute Myeloid Leukemia. , 2021, American journal of clinical pathology.

[11]  G. Inghirami,et al.  Comparison of Multiple Clinical Testing Modalities for Assessment of NPM1-Mutant AML , 2021, Frontiers in Oncology.

[12]  J. Kanda,et al.  Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia , 2021, Blood advances.

[13]  H. Einsele,et al.  CEBPA Mutations in 4708 Patients with Acute Myeloid Leukemia - Differential Impact of bZIP and TAD Mutations on Outcome. , 2021, Blood.

[14]  G. Juliusson,et al.  Mutational spectrum of de novo NPM1-mutated acute myeloid leukemia patients older than 75 years , 2021, Leukemia & lymphoma.

[15]  R. Marasca,et al.  NPM1-Mutated Myeloid Neoplasms with <20% Blasts: A Really Distinct Clinico-Pathologic Entity? , 2020, International journal of molecular sciences.

[16]  M. Konopleva,et al.  Prognostic and therapeutic impacts of mutant TP53 variant allelic frequency in newly diagnosed acute myeloid leukemia. , 2020, Blood advances.

[17]  B. Falini,et al.  NPM1-mutated acute myeloid leukemia: from bench to bedside. , 2020, Blood.

[18]  M. Walter,et al.  Genetics of Progression from MDS to Secondary Leukemia. , 2020, Blood.

[19]  M. Konopleva,et al.  Outcomes of older patients with NPM1-mutated AML: current treatments and the promise of venetoclax-based regimens. , 2020, Blood advances.

[20]  Benjamin L. Ebert,et al.  Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes , 2019, Nature Medicine.

[21]  T. Haferlach,et al.  Molecular Classification of AML-MRC Reveals a Distinct Profile and Identifies MRC-like Patients with Poor Overall Survival , 2019, Blood.

[22]  M. Konopleva,et al.  NPM1 mutant variant allele frequency correlates with leukemia burden but does not provide prognostic information in NPM1‐mutated acute myeloid leukemia , 2019, American journal of hematology.

[23]  W. Wong,et al.  Clinicopathologic and genetic characterization of nonacute NPM1-mutated myeloid neoplasms. , 2019, Blood advances.

[24]  B. Bain,et al.  Morphological and Immunophenotypic Clues to the WHO Categories of Acute Myeloid Leukaemia , 2019, Acta Haematologica.

[25]  M. Konopleva,et al.  NPM1 mutations define a specific subgroup of MDS and MDS/MPN patients with favorable outcomes with intensive chemotherapy. , 2019, Blood advances.

[26]  A. Letai,et al.  Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. , 2019, Blood.

[27]  G. Del Sal,et al.  Mutant p53 as a guardian of the cancer cell , 2018, Cell Death & Differentiation.

[28]  W. Hiddemann,et al.  NPM1 Variant Allele Frequency and Outcomes in AML , 2018, Blood.

[29]  K. Ballman,et al.  Somatic mutations precede acute myeloid leukemia years before diagnosis , 2018, Nature Medicine.

[30]  Stanley W. K. Ng,et al.  Prediction of acute myeloid leukaemia risk in healthy individuals , 2018, Nature.

[31]  T. Graubert,et al.  High NPM1-mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML. , 2018, Blood.

[32]  C. Preudhomme,et al.  NPM1 mutation is not associated with prolonged complete remission in acute myeloid leukemia patients treated with hypomethylating agents , 2018, Haematologica.

[33]  C. Bloomfield,et al.  Mutation patterns identify adult patients with de novo acute myeloid leukemia aged 60 years or older who respond favorably to standard chemotherapy: an analysis of Alliance studies , 2018, Leukemia.

[34]  Traci M. Blonquist,et al.  Association of mutations with morphological dysplasia in de novo acute myeloid leukemia without 2016 WHO Classification-defined cytogenetic abnormalities , 2018, Haematologica.

[35]  Wei Li,et al.  Mutational spectrum of acute myeloid leukemia patients with double CEBPA mutations based on next-generation sequencing and its prognostic significance , 2018, Oncotarget.

[36]  A. Feber,et al.  Variable outcome and methylation status according to CEBPA mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment , 2017, Haematologica.

[37]  A. Tefferi,et al.  Nucleophosmin 1 (NPM1) mutations in chronic myelomonocytic leukemia and their prognostic relevance , 2017, American journal of hematology.

[38]  M. Konopleva,et al.  More than 1 TP53 abnormality is a dominant characteristic of pure erythroid leukemia. , 2017, Blood.

[39]  Bob Löwenberg,et al.  Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. , 2017, Blood.

[40]  S. Miyano,et al.  Dynamics of clonal evolution in myelodysplastic syndromes , 2016, Nature Genetics.

[41]  Rashmi Kanagal-Shamanna,et al.  TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes , 2016, Cancer.

[42]  M. Chiarini,et al.  CEBPA–double-mutated acute myeloid leukemia displays a unique phenotypic profile: a reliable screening method and insight into biological features , 2016, Haematologica.

[43]  U. Jaeger,et al.  Karyotype plus NPM1 mutation status defines a group of elderly patients with AML (≥60 years) who benefit from intensive post‐induction consolidation therapy , 2016, American journal of hematology.

[44]  W. Hiddemann,et al.  Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. , 2016, Blood.

[45]  Nicola D. Roberts,et al.  Genomic Classification and Prognosis in Acute Myeloid Leukemia. , 2016, The New England journal of medicine.

[46]  J. Merker,et al.  Next-generation sequencing of acute myeloid leukemia identifies the significance of TP53, U2AF1, ASXL1, and TET2 mutations , 2015, Modern Pathology.

[47]  D. Birnbaum,et al.  Role of ASXL1 and TP53 mutations in the molecular classification and prognosis of acute myeloid leukemias with myelodysplasia-related changes , 2015, Oncotarget.

[48]  D. Neuberg,et al.  Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. , 2015, Blood.

[49]  E. Zeggini,et al.  Leukemia-Associated Somatic Mutations Drive Distinct Patterns of Age-Related Clonal Hemopoiesis , 2015, Cell reports.

[50]  M. McCarthy,et al.  Age-related clonal hematopoiesis associated with adverse outcomes. , 2014, The New England journal of medicine.

[51]  T. Haferlach,et al.  In AML Secondary to MDS NPM1 Mutations Are Late Events, Less Frequent, and Associated with a Different Pattern of Molecular Mutations Than in De Novo AML , 2014 .

[52]  A. Cherry,et al.  Acute myeloid leukemia with monosomal karyotype: morphologic, immunophenotypic, and molecular findings. , 2014, American journal of clinical pathology.

[53]  Lincoln D. Stein,et al.  Identification of pre-leukemic hematopoietic stem cells in acute leukemia , 2014, Nature.

[54]  I. Weissman,et al.  Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission , 2014, Proceedings of the National Academy of Sciences.

[55]  M. Stratton,et al.  Clinical and biological implications of driver mutations in myelodysplastic syndromes. , 2013, Blood.

[56]  C Haferlach,et al.  Landscape of genetic lesions in 944 patients with myelodysplastic syndromes , 2013, Leukemia.

[57]  L. Bullinger,et al.  Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. , 2013, Blood.

[58]  Yuehua Wu,et al.  Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia , 2013, Modern Pathology.

[59]  Benjamin J. Raphael,et al.  Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. , 2013, The New England journal of medicine.

[60]  Je-Hwan Lee,et al.  Association of cup-like nuclei in blasts with FLT3 and NPM1 mutations in acute myeloid leukemia , 2013, Annals of Hematology.

[61]  Joshua F. McMichael,et al.  The Origin and Evolution of Mutations in Acute Myeloid Leukemia , 2012, Cell.

[62]  D. Birnbaum,et al.  Acute myeloid leukemia with myelodysplasia‐related changes are characterized by a specific molecular pattern with high frequency of ASXL1 mutations , 2012, American journal of hematology.

[63]  N. Socci,et al.  Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. , 2012, The New England journal of medicine.

[64]  U. Moll,et al.  Links between mutant p53 and genomic instability , 2012, Journal of cellular biochemistry.

[65]  K. Döhner,et al.  Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies. , 2012, Blood.

[66]  J. Esteve,et al.  Immunophenotype of acute myeloid leukemia with NPM mutations: prognostic impact of the leukemic compartment size. , 2011, Leukemia research.

[67]  J. Esteve,et al.  The prognostic value of multilineage dysplasia in de novo acute myeloid leukemia patients with intermediate-risk cytogenetics is dependent on NPM1 mutational status. , 2010, Blood.

[68]  J. Licht,et al.  Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. , 2010, Cancer cell.

[69]  R. Hills,et al.  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. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[70]  Paola Fazi,et al.  Multilineage dysplasia has no impact on biologic, clinicopathologic, and prognostic features of AML with mutated nucleophosmin (NPM1). , 2010, Blood.

[71]  E. Hoster,et al.  Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[72]  K Holzmann,et al.  Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis , 2010, Leukemia.

[73]  Bas J. Wouters,et al.  Brief Report Results and Discussion , 2022 .

[74]  T. Pabst,et al.  Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis , 2009, British Journal of Cancer.

[75]  A. Hagemeijer,et al.  Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[76]  Axel Benner,et al.  Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. , 2008, The New England journal of medicine.

[77]  R. Arceci,et al.  The incidence and clinical significance of nucleophosmin mutations in childhood AML. , 2007, Blood.

[78]  Brunangelo Falini,et al.  Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. , 2007, Blood.

[79]  E. Hoster,et al.  NPM1 but not FLT3-ITD mutations predict early blast cell clearance and CR rate in patients with normal karyotype AML (NK-AML) or high-risk myelodysplastic syndrome (MDS). , 2006, Blood.

[80]  Myriam Alcalay,et al.  Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia. , 2006, Blood.

[81]  B. Cheson,et al.  Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. , 2006, Blood.

[82]  Pier Paolo Pandolfi,et al.  Nucleophosmin and cancer , 2006, Nature Reviews Cancer.

[83]  W. Hiddemann,et al.  Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML. , 2006, Blood.

[84]  D. Steensma,et al.  C‐terminal nucleophosmin mutations are uncommon in chronic myeloid disorders , 2006, British journal of haematology.

[85]  Bob Löwenberg,et al.  Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. , 2005, Blood.

[86]  P. Pandolfi,et al.  Role of nucleophosmin in embryonic development and tumorigenesis , 2005, Nature.

[87]  Paola Fazi,et al.  Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. , 2005, The New England journal of medicine.

[88]  C. Nerlov.  C/EBPα mutations in acute myeloid leukaemias , 2004, Nature Reviews Cancer.

[89]  L. Shih,et al.  Acquisition of FLT3 or N-ras mutations is frequently associated with progression of myelodysplastic syndrome to acute myeloid leukemia , 2004, Leukemia.

[90]  S. Fröhling,et al.  CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[91]  J. Cayuela,et al.  Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). , 2002, Blood.

[92]  N. Harris,et al.  The World Health Organization (WHO) classification of the myeloid neoplasms. , 2002, Blood.

[93]  J. Griffin,et al.  The roles of FLT3 in hematopoiesis and leukemia. , 2002, Blood.

[94]  S. Fröhling,et al.  Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16 to 60 years old with acute myeloid leukemia and normal cytogenetics: a study of the Acute Myeloid Leukemia Study Group Ulm. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[95]  Pier Giuseppe Pelicci,et al.  Nucleophosmin regulates the stability and transcriptional activity of p53 , 2002, Nature Cell Biology.

[96]  D. Grimwade,et al.  The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. , 2001, Blood.

[97]  T. Naoe,et al.  Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. , 2001, Blood.

[98]  Pu Zhang,et al.  Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-α (C/EBPα), in acute myeloid leukemia , 2001, Nature Genetics.

[99]  H. Kaneko,et al.  Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. , 1996, Leukemia.

[100]  W. Hiddemann,et al.  De novo AML with dysplastic hematopoiesis: cytogenetic and prognostic significance. , 1996, Leukemia.

[101]  M. Caligiuri,et al.  Molecular rearrangement of the ALL-1 gene in acute myeloid leukemia without cytogenetic evidence of 11q23 chromosomal translocations. , 1994, Cancer research.

[102]  G Flandrin,et al.  Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. , 1985, Annals of internal medicine.

[103]  H. Gralnick,et al.  Proposals for the Classification of the Acute Leukaemias French‐American‐British (FAB) Co‐operative Group , 1976, British journal of haematology.

[104]  M. Olson,et al.  Phosphorylation of acid-soluble proteins in isolated nucleoli of Novikoff hepatoma ascites cells. Effects of divalent cations. , 1974, The Journal of biological chemistry.

[105]  C. Chao.  Mechanisms of p53 degradation. , 2015, Clinica chimica acta; international journal of clinical chemistry.

[106]  S. Fröhling,et al.  TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. , 2012, Blood.

[107]  L. Medeiros,et al.  FLT3 and NPM1 mutations in myelodysplastic syndromes: Frequency and potential value for predicting progression to acute myeloid leukemia. , 2011, American journal of clinical pathology.

[108]  M. Yao,et al.  Clinical and biological implications of partial tandem duplication of the MLL gene in acute myeloid leukemia without chromosomal abnormalities at 11q23 , 2002, Leukemia.