NGS e malattie mieloproliferative

Matteo G Della Porta Department of Hematology Oncology,

Fondazione IRCCS Policlinico S. Matteo, University of Pavia Medical School,

Pavia, Italy matteo@haematologica.org

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