Advertisement

Predictive and Prognostic Biomarkers in Myeloid Neoplasms

  • Raju K. Pillai
Chapter

Abstract

The major categories of myeloid neoplasms include myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN, acute myeloid leukemia (AML), mastocytosis, blastic plasmacytoid dendritic cell neoplasms, and myeloid/lymphoid neoplasms with eosinophilia. MPNs are stem cell disorders characterized by proliferation of cells of one or more of the myeloid lineages (granulocytic, erythroid, and megakaryocytic) and a tendency to transform to acute myeloid leukemia. Dysregulation of JAK2 signaling by direct or indirect mechanisms has emerged as the central theme in classic MPNs leading to the use of JAK2 inhibitors for therapy. MDS are clonal hematopoietic neoplasms characterized by simultaneous proliferation and apoptosis of hematopoietic cells that results in a normocellular or hypercellular marrow with peripheral blood cytopenias and a tendency to evolve into acute myeloid leukemia. Sequential acquisition of somatic mutations in a set of genes involved in hematopoiesis leads to dysregulation of cellular processes leading to asymptomatic clonal hematopoiesis and later to MDS. MDS/MPNs include clonal myeloid neoplasms, which at the time of initial presentation are associated with features that support the diagnosis of MDS and other findings more consistent with an MPN. AML results from the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, or tissues. Mutations in the epigenetic pathway including genes such as DNMT3A, ASXL1, TET2, and IDH1/IDH2 are acquired early in the disease process. Mutations involving the signal transduction pathway or NPM1 are typically secondary events that occur later during the evolution of the disease. Inhibitors of FLT3 and IDH1 and IDH2 are currently used for targeted therapy.

Keywords

Myeloproliferative neoplasm Chronic myeloid leukemia Polycythemia vera Essential thrombocythemia Primary myelofibrosis Myelodysplastic syndrome Myelodysplastic/myeloproliferative neoplasm Chronic myelomonocytic leukemia Mastocytosis Acute myeloid leukemia 

References

  1. 1.
    Levine RL, Pardanani A, Tefferi A, et al. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer. 2007;7(9):673–83.CrossRefPubMedGoogle Scholar
  2. 2.
    Kennedy JA, Ebert BL. Clinical implications of genetic mutations in myelodysplastic syndrome. J Clin Oncol. 2017;35(9):968–74.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Baxter EJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054–61.CrossRefPubMedGoogle Scholar
  4. 4.
    James C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):1144–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Kralovics R, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352(17):1779–90.CrossRefPubMedGoogle Scholar
  6. 6.
    Defour JP, et al. Oncogenic activation of MPL/thrombopoietin receptor by 17 mutations at W515: implications for myeloproliferative neoplasms. Leukemia. 2016;30(5):1214–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Papaemmanuil E, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122(22):3616–27; quiz 3699.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Yoshida K, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011;478(7367):64–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Delhommeau F, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360(22):2289–301.CrossRefPubMedGoogle Scholar
  10. 10.
    Losman JA, et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. 2013;339(6127):1621–5.CrossRefPubMedGoogle Scholar
  11. 11.
    Haferlach T, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28(2):241–7.CrossRefPubMedGoogle Scholar
  12. 12.
    West AH, Godley LA, Churpek JE. Familial myelodysplastic syndrome/acute leukemia syndromes: a review and utility for translational investigations. Ann N Y Acad Sci. 2014;1310:111–8.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Ok CY, et al. TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases. J Hematol Oncol. 2015;8:45.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Aldoss I, et al. Favorable impact of allogeneic stem cell transplantation in patients with therapy-related myelodysplasia regardless of TP53 mutational status. Haematologica. 2017;102(12):2030–8.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. J Clin Oncol. 2001;19(5):1405–13.CrossRefPubMedGoogle Scholar
  16. 16.
    Busque L, et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet. 2012;44(11):1179–81.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Link DC, Walter MJ. ‘CHIP’ping away at clonal hematopoiesis. Leukemia. 2016;30(8):1633–5.CrossRefPubMedGoogle Scholar
  18. 18.
    Bejar R. CHIP, ICUS, CCUS and other four-letter words. Leukemia. 2017;31(9):1869–71.CrossRefPubMedGoogle Scholar
  19. 19.
    Steensma DP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9–16.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Cancer Genome Atlas Research, N, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74.CrossRefGoogle Scholar
  21. 21.
    Patel JP, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079–89.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Dufour A, et al. Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. J Clin Oncol. 2010;28(4):570–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Thiede C, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006;107(10):4011–20.CrossRefPubMedGoogle Scholar
  24. 24.
    Tang JL, 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):5352–61.CrossRefPubMedGoogle Scholar
  25. 25.
    Renneville A, et al. Wilms tumor 1 gene mutations are associated with a higher risk of recurrence in young adults with acute myeloid leukemia: a study from the Acute Leukemia French Association. Cancer. 2009;115(16):3719–27.CrossRefPubMedGoogle Scholar
  26. 26.
    Gaidzik VI, et al. TET2 mutations in acute myeloid leukemia (AML): results from a comprehensive genetic and clinical analysis of the AML study group. J Clin Oncol. 2012;30(12):1350–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Paschka P, et al. ASXL1 mutations in younger adult patients with acute myeloid leukemia: a study by the German-Austrian Acute Myeloid Leukemia Study Group. Haematologica. 2015;100(3):324–30.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Boissel N, et al. Prognostic impact of isocitrate dehydrogenase enzyme isoforms 1 and 2 mutations in acute myeloid leukemia: a study by the Acute Leukemia French Association group. J Clin Oncol. 2010;28(23):3717–23.CrossRefPubMedGoogle Scholar
  29. 29.
    Bowen D, et al. TP53 gene mutation is frequent in patients with acute myeloid leukemia and complex karyotype, and is associated with very poor prognosis. Leukemia. 2009;23(1):203–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Papaemmanuil E, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–21.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Dohner H, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Stein EM, Tallman MS. Emerging therapeutic drugs for AML. Blood. 2016;127(1):71–8.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of PathologyCity of Hope National Medical CenterDuarteUSA

Personalised recommendations