Clinical significance of the whole-exome studies in myeloid neoplasms using next-generation sequencing

S.A. Smirnikhina1, A.V. Lavrov1, E.P. Adilgereeva1, A.G. Turkina2, S.I. Kutsev1,3

1 FSBI «Research Centre for Medical Genetics» RAMS, Moscow, Russian Federation

2 FSBI «Hematological Research Centre» Russian Ministry of Health, Moscow, Russian Federation

3 SBEI HPE «Russian National Research Medical University n.a. N.I. Pirogov» Russian Ministry of Health, Moscow, Russian Federation


The application of next generation sequencing (NGS) to study myeloid neoplasms pathogenesis is considered in this review. Analysis of tumor cell’s exome in patients with different forms of hematopoietic myeloid tumors revealed new recurrent mutations, significant for the understanding of molecular mechanisms of pathogenesis, estimation of therapy effectiveness prognosis, development the new approaches to target therapy of these diseases.

Keywords: exome, next generation sequencing, myeloid neoplasms.

Read in PDF (RUS)pdficon


  1. Hochhaus A., O’Brien S.G., Guilhot F. et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009; 23(6): 1054–61.
  2. Choi M., Scholl U.I., Ji W. et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc. Natl. Acad. Sci. USA 2009; 106(45): 19096–101.
  3. Rothberg J.M., Hinz W., Rearick T.M. et al. An integrated semiconductor device enabling non-optical genome sequencing. Nature 2011; 475(7356): 348–52.
  4. Ng S.B., Turner E.H., Robertson P.D. et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 2009; 461(7261): 272–6.
  5. Ng S.B., Buckingham K.J., Lee C. et al. Exome sequencing identifies the cause of a Mendelian disorder. Nat. Genet. 2010; 42(1): 30–5.
  6. Kahvejian A., Quackenbush J., Thompson J.F. What would you do if you could sequence everything? Nat. Biotechnol. 2008; 26(10): 1125–33.
  7. Biesecker L.G. Exome sequencing makes medical genomics a reality. Nat. Genet. 2010; 42(1): 13–4.
  8. Gregory T.K., Wald D., Chen Y. et al. Molecular prognostic markers for adult acute myeloid leukemia with normal cytogenetics. J. Hematol. Oncol. 2009; 2: 23.
  9. Riva L., Luzi L., Pelicci P.G. Genomics of acute myeloid leukemia: the next generation. Front Oncol. 2012; 2: 40.
  10. Walter M.J., Payton J.E., Ries R.E. et al. Acquired copy number alterations in adult acute myeloid leukemia genomes. Proc. Natl. Acad. Sci. USA 2009; 106(31): 12950–5.
  11. Walter M.J., Graubert T.A., Dipersio J.F. et al. Next-generation sequencing of cancer genomes: back to the future. Per. Med. 2009; 6(6): 653.
  12. Mrozek K., Heerema N.A., Bloomfield C.D. Cytogenetics in acute leukemia. Blood Rev. 2004; 18: 115–36.
  13. Kelly L.M., Kutok J.L., Williams I.R. et al. PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc. Natl. Acad. Sci. USA 2002; 99: 8283–8.
  14. Ley T.J., Mardis E.R., Ding L. et al. DNA sequencing of a cytogenetically normal acute myeloid leukemia genome. Nature 2008; 456(7218): 66–72.
  15. Arber D.A., Brunning R.D., Le Beau M.M. et al. Acute myeloid leukaemia with recurrent genetic abnormalities. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. Ed. by S. Swerdlow, E. Campo, N.L. Harris. Geneva: IARC Press, 2008: 110–23.
  16. Mardis E.R., Ding L., Dooling D.J. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 2009; 361(11): 1058–66.
  17. Ley T.J., Ding L., Walter M.J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 2010; 363(25): 2424–33.
  18. Grossmann V., Tiacci E., Holmes A.B. et al. Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. Blood 2011; 118(23): 6153–63.
  19. Jan M., Snyder T.M., Corces-Zimmerman M.R. et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci. Transl. Med. 2012; 4(149): 149ra118.
  20. Thol F., Kolking B., Damm F. et al. Next-generation sequencing for minimal residual disease monitoring in acute myeloid leukemia patients with FLT3-ITD or NPM1 mutations. Genes Chromos. Cancer 2012; 51(7): 689–95.
  21. Duncavage E.J., Abel H.J., Szankasi P. et al. Targeted next generation sequencing of clinically significant gene mutations and translocations in leukemia. Mod. Pathol. 2012; 25(6): 795–804.
  22. Mardis E.R., Wilson R.K. Cancer genome sequencing: a review. Hum. Mol. Genet. 2009; 18(R2): R163–8.
  23. Papaemmanuil E., Cazzola M., Boultwood J. et al. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N. Engl. J. Med. 2011; 365(15): 1384–95.
  24. Malcovati L., Papaemmanuil E., Bowen D.T. et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood 2011; 118(24): 6239–46.
  25. Visconte V., Rogers H.J., Singh J. et al. SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes. Blood 2012 Jul 23. [Epub ahead of print]
  26. Yoshida K., Sanada M., Shiraishi Y. et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011; 478(7367): 64–9.
  27. Makishima H., Visconte V., Sakaguchi H. et al. Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 2012; 119(14): 3203–10.
  28. Graubert T.A., Shen D., Ding L. et al. Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat. Genet. 2011; 44(1): 53–7.
  29. Albert B.J., McPherson P.A., O’Brien K. et al. Meayamycin inhibits pre-messenger RNA splicing and exhibits picomolar activity against multidrugresistant cells. Mol. Cancer Ther. 2009; 8(8): 2308–18.
  30. Visconte V., Makishima H., Maciejewski J.P., Tiu R.V. Emerging roles of the spliceosomal machinery in myelodysplastic syndromes and other hematological disorders. Leukemia 2012 May 15. doi: 10.1038/leu.2012.130. [Epub ahead of print]
  31. Tallman M.S., Kim H.T., Paietta E. et al. Acute monocytic leukemia (French-American-British classification M5) does not have a worse prognosis than other subtypes of acute myeloid leukemia: a report from the Eastern Cooperative Oncology Group. J. Clin. Oncol. 2004; 22: 1276–86.
  32. Yan X.J., Xu J., Gu Z.H. et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat. Genet. 2011; 43(4): 309–15.
  33. Grimwade D., Biondi A., Mozziconacci M.J. et al. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Francais de Cytogenetique Hematologique, Groupe de Francais d’Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action «Molecular Cytogenetic Diagnosis in Haematological Malignancies». Blood 2000; 96(4): 1297–308.
  34. Greif P.A., Yaghmaie M., Konstandin N.P. et al. Somatic mutations in acute promyelocytic leukemia (APL) identified by exome sequencing. Leukemia 2011; 25(9): 1519–22.
  35. Welch J.S., Westervelt P., Ding L. et al. Use of whole-genome sequencing to diagnose a cryptic fusion oncogene. JAMA 2011; 305(15): 1577–84.
  36. Spector M.S., Iossifov I., Kritharis A. et al. Mast-cell leukemia exome chain and KITbsequencing reveals a mutation in the IgE mast-cell receptor V654A. Leukemia 2012; 26(6): 1422–5.
  37. Kohlmann A., Grossmann V., Klein H.U. et al. Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. J. Clin. Oncol. 2010; 28(24): 3858–65.
  38. Kohlmann A., Klein H.U., Weissmann S. et al. The Interlaboratory RObustness of Next-generation sequencing (IRON) study: a deep sequencing investigation of TET2, CBL and KRAS mutations by an international consortium involving 10 laboratories. Leukemia 2011; 25(12): 1840–8.