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Recent Discoveries in Molecular Characterization of Acute Myeloid Leukemia

  • Acute Leukemias (F Ravandi, Section Editor)
  • Published:
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Abstract

Acute myeloid leukemia (AML) is a clinically heterogeneous disease, yet it is one of the most molecularly well-characterized cancers. Risk stratification of patients currently involves determination of the presence of cytogenetic abnormalities in combination with molecular genetic testing in a few genes. Several new recurrent genetic molecular abnormalities have recently been identified, including TET2, ASXL1, IDH1, IDH2, DNMT3A, and PHF6. Mutational analyses have identified that patients with DNMT3A or NPM1 mutations or MLL translocation have improved overall survival with high-dose chemotherapy. Mutational profiling can refine prognostication, particularly for patients in the intermediate-risk group or with a normal karyotype. CD25 expression status improves prognostic risk classification in AML independent of established biomarkers. Biomarkers such as 2- hydroxyglutarate in IDH1/2-mutant AML patients predict patient responses and minimal residual disease. These recent discoveries are being incorporated into our existing molecular risk stratification as well as the exploration of new therapeutics directed to these molecular targets.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Dohner H, Estey EH, Amadori S, 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;115:453–74.

    Article  PubMed  Google Scholar 

  2. Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1909–18.

    Article  CAS  PubMed  Google Scholar 

  3. Schnittger S, Kohl TM, Haferlach T, et al. KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood. 2006;107:1791–9.

    Article  CAS  PubMed  Google Scholar 

  4. Paschka P, Marcucci G, Ruppert AS, et al. 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;24:3904–11.

    Article  CAS  PubMed  Google Scholar 

  5. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363:2424–33. This manuscript presents the initial identification of mutations in DNMT3A in AML as well as their clinical relevance. DNMT3A mutations are amongst the most common somatic mutations in AML and impart adverse prognostic impact (none of which was known until publication of this manuscript).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. 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;43:309–15.

    Article  CAS  PubMed  Google Scholar 

  7. Yamashita Y, Yuan J, Suetake I, et al. Array-based genomic resequencing of human leukemia. Oncogene. 2010;29:3723–31.

    Article  CAS  PubMed  Google Scholar 

  8. Thol F, Damm F, Ludeking A, et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol. 2011;29:2889–96.

    Article  CAS  PubMed  Google Scholar 

  9. Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361:1058–66.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Gross S, Cairns RA, Minden MD, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010;207:339–44.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. 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;17:225–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Green CL, Evans CM, Zhao L, et al. The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood. 2011;118:409–12.

    Article  CAS  PubMed  Google Scholar 

  13. Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079–89. This manuscript analyzed the clinical and therapeutic relevance of 18 recurrently mutated in genes in AML patients age 16-60 years-old uniformly treated on the ECOG E1900 study. The study identified genetic alterations which predicted for differential response to high-dose induction chemotherapy in AML.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Abbas S, Lugthart S, Kavelaars FG, et al. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia (AML): prevalence and prognostic value. Blood. 2010;116:2122–6.

    Article  CAS  PubMed  Google Scholar 

  15. Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 2010;28:3636–43.

    Article  CAS  PubMed  Google Scholar 

  16. Green CL, Evans CM, Hills RK, Burnett AK, Linchl DC, Gale RE. The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status. Blood. 2010;116(15):2779–82.

    Article  CAS  PubMed  Google Scholar 

  17. Ward PS, Cross JR, Lu C, et al. Identification of additional IDH mutations associated with oncometabolite R(-)-2-hydroxyglutarate production. Oncogene. 2012;31:2491–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289–301.

    Article  PubMed  Google Scholar 

  19. Abdel-Wahab O, Patel J, Levine RL. Clinical implications of novel mutations in epigenetic modifiers in AML. Hematol Oncol Clin N Am. 2011;25:1119–33.

    Article  Google Scholar 

  20. 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;18:553–67.

    Article  CAS  PubMed  Google Scholar 

  21. Chou WC, Chou SC, Liu CY, et al. TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood. 2011;118:3803–10.

    Article  CAS  PubMed  Google Scholar 

  22. 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;29:1373–81.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Gelsi-Boyer V, Trouplin V, Adelaide J, et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol. 2009;145:788–800.

    Article  CAS  PubMed  Google Scholar 

  24. 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;118:6920–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Pratcorona M, Abbas S, Sanders MA, et al. Acquired mutations in ASXL1 in acute myeloid leukemia: prevalence and prognostic value. Haematologica. 2012;97:388–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Van Vlierberghe P, Palomero T, Khiabanian H, et al. PHF6 mutations in T-cell acute lymphoblastic leukemia. Nat Genet. 2010;42:338–42.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Van Vlierberghe P, Patel J, Abdel-Wahab O, et al. PHF6 mutations in adult acute myeloid leukemia. Leukemia. 2011;25:130–4.

    Article  PubMed  Google Scholar 

  28. DiNardo CD, Propert KJ, Loren AW, et al. Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. Blood. 2013;121:4917–24.

    Article  CAS  PubMed  Google Scholar 

  29. Wang JH, Chen WL, Li JM, et al. Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China. Proc Natl Acad Sci U S A. 2013;110:17017–22.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Janin M, Mylonas E, Saada V, et al. Serum 2-hydroxyglutarate production in IDH1- and IDH2-mutated de novo acute myeloid leukemia: a study by the acute leukemia French Association Group. J Clin Oncol. 2013;32:297–305.

    Article  PubMed  Google Scholar 

  31. Fathi AT, Sadrzadeh H, Borger DR, et al. Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and therapeutic response. Blood. 2012;120:4649–52.

    Article  CAS  PubMed  Google Scholar 

  32. Gönen M, Sun Z, Figueroa ME, et al. CD25 expression status improves prognostic risk classification in AML independent of established biomarkers: ECOG phase 3 trial, E1900. Blood. 2012;120:2297–306.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Rockova V, Abbas S, Wouters BJ, et al. Risk stratification of intermediate-risk acute myeloid leukemia: integrative analysis of a multitude of gene mutation and gene expression markers. Blood. 2011;118:1069–76.

    Article  CAS  PubMed  Google Scholar 

  34. Pierceall WE, Kornblau SM, Carlson NE, et al. BH3 profiling discriminates response to cytarabine-based treatment of acute myelogenous leukemia. Mol Cancer Ther. 2013;12:2940–9.

    Article  CAS  PubMed  Google Scholar 

  35. Ley TJ, Miller C, Ding L, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059-74. This manuscript presented whole genome and whole exome sequencing data from 200 AML patients, the largest study of its kind to date. The data from this study presents the most comprehensive list of recurrently mutated genes in AML at this time.

  36. Yoshida K, Sanada M, Shiraishi Y, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478:64–9. This manuscript was the first paper to identify recurrent mutations in spliceosomal proteins in patients with myeloid malignancies. Subsequent studies have identified spliceosomal mutations in particular subsets of patients with MDS and chronic lymphocytic leukemia.

    Article  CAS  PubMed  Google Scholar 

  37. Zhang SJ, Rampal R, Manshouri T, et al. Genetic analysis of patients with leukemic transformation of myeloproliferative neoplasms shows recurrent SRSF2 mutations that are associated with adverse outcome. Blood. 2012;119:4480–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Rocquain J, Gelsi-Boyer V, Adelaide J, et al. Alteration of cohesin genes in myeloid diseases. Am J Hematol. 2010;85:717–9.

    Article  CAS  PubMed  Google Scholar 

  39. Bullinger L, Kronke J, Schon C, et al. Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis. Leukemia. 2010;24:438–49.

    Article  CAS  PubMed  Google Scholar 

  40. Walter MJ, Payton JE, Ries RE, et al. Acquired copy number alterations in adult acute myeloid leukemia genomes. Proc Natl Acad Sci U S A. 2009;106:12950–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Kon A, Shih LY, Minamino M, et al. Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. Nat Genet. 2013;45:1232–7.

    Article  CAS  PubMed  Google Scholar 

  42. Thol F, Bollin R, Gehlhaar M, et al. Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications. Blood. 2013;123:914–20.

    Article  PubMed  Google Scholar 

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Conflict of Interest

Dr. Mohamad K. Khasawneh is a board member for Incyte and Onyx. Dr. Khasawneh received honoraria from BMS, Onyx, and Celgene.

Dr. Omar Abdel-Wahab declares no potential conflicts of interest relevant to this article.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Edwards Comprehensive Cancer Center, Department of Oncological Sciences, Marshall University School of Medicine, 1400 Hal Greer Blvd, Huntington, WV, 25701-4114, USA

    Mohamad K. Khasawneh

  2. Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, 1275 York Ave, New York, NY, 10065, USA

    Omar Abdel-Wahab

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  1. Mohamad K. Khasawneh
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  2. Omar Abdel-Wahab
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Correspondence to Mohamad K. Khasawneh.

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Khasawneh, M.K., Abdel-Wahab, O. Recent Discoveries in Molecular Characterization of Acute Myeloid Leukemia. Curr Hematol Malig Rep 9, 93–99 (2014). https://doi.org/10.1007/s11899-014-0200-y

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  • DOI: https://doi.org/10.1007/s11899-014-0200-y

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