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Leukemic evolution of polycythemia vera and essential thrombocythemia: genomic profiles predict time to transformation

Damien Paz 1, 2, 3, * Rébecca Jouanneau-Courville 2, 3 Jeremie Riou 4 Jean-Christophe Ianotto 3, 5 Françoise Boyer 3, 6 Aurélie Chauveau 3, 7, 8 Maxime Renard 1, 2, 3 Jean-Claude Chomel 3, 9 Emilie Cayssials 3, 10 Maria-Pilar Gallego-Hernanz 3, 10 Cédric Pastoret 3, 11 Anne Murati 12 Frédéric Courtier 12 Marie-Christine Rousselet 13 Isabelle Quintin-Roué 14 Laurane Cottin 1, 2, 3 Corentin Orvain 3, 6 Sylvain Thépot 1, 3, 6 Jean-Marie Chrétien 15 Yves Delneste 1 Norbert Ifrah 1, 3, 6 Odile Blanchet 1, 2, 3, 16 Mathilde Hunault-Berger 1, 3, 6 Eric Lippert 3, 7, 8 Valérie Ugo 1, 2, 3
Abstract : Among myeloproliferative neoplasms, polycythemia vera (PV) and essential thrombocythemia (ET) are the 2 entities associated with the most chronic disease course. Leukemic evolution occurs rarely but has a grim prognosis. The interval between diagnosis and leukemic evolution is highly variable, from a few years to .20 years. We performed a molecular evaluation of 49 leukemic transformations of PV and ET by targeted next-generation sequencing. Using a hierarchical classification, we identified 3 molecular groups associated with a distinct time to leukemic transformation. Short-term transformations were mostly characterized by a complex molecular landscape and mutations in IDH1/2, RUNX1, and U2AF1 genes, whereas long-term transformations were associated with mutations in TP53, NRAS, and BCORL1 genes. Studying paired samples from chronic phase and transformation, we detected some mutations already present during the chronic phase, either with a significant allele burden (short-term transformation) or with a very low allele burden (especially TP53 mutations). However, other mutations were not detected even 1 year before leukemic transformation. Our results suggest that the leukemic transformation of PV and ET may be driven by distinct time-dependent molecular mechanisms.
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Damien Paz, Rébecca Jouanneau-Courville, Jeremie Riou, Jean-Christophe Ianotto, Françoise Boyer, et al.. Leukemic evolution of polycythemia vera and essential thrombocythemia: genomic profiles predict time to transformation. Blood Advances, The American Society of Hematology, 2020, 4 (19), pp.4887-4897. ⟨10.1182/bloodadvances.2020002271⟩. ⟨inserm-02970969⟩

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