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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]
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Molecular pathogenesis of Myeloid Neoplasms
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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
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Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis
Nat Genet. 2012 Sep 23. [Epub ahead of print]
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Frequency of the JAK2 V617F mutation in patients with myeloproliferative neoplasms
Cazzola M & Skoda R. Haematologica 2005;90:871-4
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Blood. 2009;114:3538-3545
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• 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
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Survival of patients with chronic myelomonocytic leukemia (CPSS score)
Blood. 2013;121: 3005-3015
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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
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Clonal architecture of chronic myelomonocytic leukemias
Blood. 2013;121(12):2186-2198)
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Nature. 2011 Sep 11;478(7367):64-9
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Genetic determinants of monocytosis in myeloid neoplasms with myelodysplasia: co-
occurrence of TET2 and SRSF2 or ZRSR2 mutations
Blood. 2014;124(9):1513-1521)
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An evolutionary perspective on chronic myelomonocytic leukemia
Leukemia (2013) 27, 1441–1450
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Clonal architecture of secondary acute myeloid leukemia
N Engl J Med 2012;366:1090-8.
NPM1, WT1, TP53, RUNX1, ASXL1 U2AF1, UMODL1
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Prognostic Score Including Gene Mutations in CMML
J Clin Oncol 31:2428-2436. © 2013
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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
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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