NGS e malattie mieloproliferative
Matteo G Della Porta Department of Hematology Oncology,
Fondazione IRCCS Policlinico S. Matteo, University of Pavia Medical School,
Pavia, Italy [email protected]
Molecular pathogenesis of Myeloid Neoplasms
Acquired mutations in TET2 in myeloid neoplasms
N Engl J Med 2009;360:2289-301; Nature Genetics 2009;41:838-842; Nature 2010;468:839-43
Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis
Nat Genet. 2012 Sep 23. [Epub ahead of print]
Frequency of the JAK2 V617F mutation in patients with myeloproliferative neoplasms
Cazzola M & Skoda R. Haematologica 2005;90:871-4
Blood. 2009;114:3538-3545
• Myeloproliferative neoplasms (MPN) Chronic myelogenous leukemia, BCR-ABL1–positive
Chronic neutrophilic leukemia
Polycythemia vera
Primary myelofibrosis
Essential thrombocythemia
Chronic eosinophilic leukemia, not otherwise specified
Mastocytosis
• Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) Chronic myelomonocytic leukemia
Atypical chronic myeloid leukemia, BCR-ABL1–negative
Juvenile myelomonocytic leukemia
Myelodysplastic/myeloproliferative neoplasm, unclassifiable
Provisional entity: RARS with marked thrombocytosis
WHO classification of MPN and MDS/MPN
Survival of patients with chronic myelomonocytic leukemia (CPSS score)
Blood. 2013;121: 3005-3015
NGS Technology Reveals a Characteristic Pattern of Molecular Mutations in 72.8% of CMML by
Detecting Frequent Alterations in TET2, CBL, RAS, and RUNX1
J Clin Oncol 28:3858-3865. © 2010
Clonal architecture of chronic myelomonocytic leukemias
Blood. 2013;121(12):2186-2198)
Nature. 2011 Sep 11;478(7367):64-9
Genetic determinants of monocytosis in myeloid neoplasms with myelodysplasia: co-
occurrence of TET2 and SRSF2 or ZRSR2 mutations
Blood. 2014;124(9):1513-1521)
An evolutionary perspective on chronic myelomonocytic leukemia
Leukemia (2013) 27, 1441–1450
Clonal architecture of secondary acute myeloid leukemia
N Engl J Med 2012;366:1090-8.
NPM1, WT1, TP53, RUNX1, ASXL1 U2AF1, UMODL1
Prognostic Score Including Gene Mutations in CMML
J Clin Oncol 31:2428-2436. © 2013
Summary The availability of NGS significantly improved our understanding of molecular architecture of MPN and MDS/MPN In MPN and MDS/MPN early driver mutations dictate future trajectories of disease evolution with distinct clinical phenotypes In CMML, TET2 mutations induce early clonal dominance (arising at the CD34+/CD38- stage of hematopoiesis, and granulomonocytic differentiation skewing of multipotent myeloid progenitors. Co-occurrence of TET2 and SRSF2 or ZRSR2 mutations showed a high specificity for myelomonocytic phenotype Additional mutations (including ASXL1) are resposnible for disease progression As in CML and JAK2+ MPN, the identification of molecular basis of MPN and MDS/MPN will allow major clinical advances in diagnosis, treatment and disease monitoring
Luca Malcovati, Ilaria Ambaglio, Marta Ubezio, Anna Gallì, Erica Travaglino, Cristiana Pascutto, Rosangela Invernizzi, Mario Cazzola.
University of Pavia Medical School
Acknowledgments
Elli Papaemmanuil Peter J Campbell
Martin Jädersten, Eva Hellström-Lindberg.
Enrica Morra Commissione REL MDS