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
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
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
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;355:2452-66.
Blood. 2009;114:3538-3545
Nature. 2011 Sep 11;478(7367):64-9
Clonal architecture of chronic myelomonocytic leukemias Blood. 2013;121(12):2186-2198)
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
Recurrent SETBP1 mutations in atypical chronic myeloid leukemia Distribution of alteration of SETBP1 protein Nature Genetics 2013
Oncogenic CSF3R Mutations in Chronic Neutrophilic Leukemia and Atypical CML N Engl J Med 2013;368:1781-90.
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
Clonal architecture of secondary acute myeloid leukemia NPM1, WT1, TP53, RUNX1, ASXL1 U2AF1, UMODL1 N Engl J Med 2012;366:1090-8.
Mutations and prognosis in PMF Leukemia (2013) 27, 1861 1869
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 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
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.