NGS e malattie mieloproliferative
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1 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
2 Molecular pathogenesis of Myeloid Neoplasms
3 WHO classification of MPN and MDS/MPN 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
4 Molecular pathogenesis of Myeloid Neoplasms
5 Acquired mutations in TET2 in myeloid neoplasms N Engl J Med 2009;360: ; Nature Genetics 2009;41: ; Nature 2010;468:839-43
6 Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis Nat Genet Sep 23. [Epub ahead of print]
7 Frequency of the JAK2 V617F mutation in patients with myeloproliferative neoplasms Cazzola M & Skoda R. Haematologica 2005;90:871-4
8 JAK2 mutation induces disease phenotype in MPN JAK2+ MPN - longer duration of disease - higher rate of complications (fibrosis, hemorrhage, and thrombosis) - Higher rate of treatment with cytoreductive therapy JAK2- MPN N Engl J Med 2006;355:
9 Blood. 2009;114:
10 Nature Sep 11;478(7367):64-9
11 Clonal architecture of chronic myelomonocytic leukemias Blood. 2013;121(12): )
12 WHO classification of MPN and MDS/MPN Myeloproliferative neoplasms (MPN) Chronic myelogenous leukemia, BCR-ABL1 positive Chronic neutrophilic leukemia Polycythemia vera Primary myelofibrosis JAK/STAT pathway gene mutations Essential thrombocythemia Mastocytosis Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) Chronic myelomonocytic leukemia TET2 and SRSF2 mutations Atypical chronic myeloid leukemia, BCR-ABL1 negative Juvenile myelomonocytic leukemia Myelodysplastic/myeloproliferative neoplasm, unclassifiable Provisional entity: RARS-T SF3B1 and JAK/STAT gene mutations
13 Recurrent SETBP1 mutations in atypical chronic myeloid leukemia Distribution of alteration of SETBP1 protein Nature Genetics 2013
14 Oncogenic CSF3R Mutations in Chronic Neutrophilic Leukemia and Atypical CML N Engl J Med 2013;368:
15 WHO classification of MPN and MDS/MPN Myeloproliferative neoplasms (MPN) Chronic myelogenous leukemia, BCR-ABL1 positive Chronic neutrophilic leukemia CSF3R gene mutations Polycythemia vera Primary myelofibrosis Essential thrombocythemia Mastocytosis Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) Chronic myelomonocytic leukemia Atypical CML, BCR-ABL1 negative SETBP1 - CSF3R mutations Juvenile myelomonocytic leukemia Myelodysplastic/myeloproliferative neoplasm, unclassifiable Provisional entity: RARS-T
16 Clonal architecture of secondary acute myeloid leukemia NPM1, WT1, TP53, RUNX1, ASXL1 U2AF1, UMODL1 N Engl J Med 2012;366:
17 Mutations and prognosis in PMF Leukemia (2013) 27,
18 Prognostic Score Including Gene Mutations in CMML J Clin Oncol 31:
19 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 The identification of specific associations between genotype and disease phenotypes is essential to come to a recognition of disease entities based on distinctive genetic profiles 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
20 Acknowledgments University of Pavia Medical School Elisa Rumi Daniela Pietra Elli Papaemmanuil Peter J Campbell Luca Malcovati, Ilaria Ambaglio, Marta Ubezio, Anna Gallì, Rosangela Invernizzi, Mario Cazzola. Martin Jädersten, Eva Hellström-Lindberg.
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