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Genomic analysis of primary and secondary myelofibrosis redefines the prognostic impact of ASXL1 mutations: a FIM study

Damien Luque Paz 1, 2, 3 Jeremie Riou 4 Emmanuelle Verger 5, 6 Bruno Cassinat 5, 6 Aurélie Chauveau 7 Jean-Christophe Ianotto 8 Brigitte Dupriez 9 Françoise Boyer 10 Maxime Renard 1, 2, 3 Olivier Mansier 11, 12 Anne Murati 13 Jérôme Rey 14 Gabriel Etienne 15 Véronique Mansat-de Mas 7 Suzanne Tavitian 16 Olivier Nibourel 17, 18 Stéphane Girault 19 yannick Le Bris 20, 21 François Girodon 22 Dana Ranta 23 Jean-Claude Chomel 24 Pascale Cony-Makhoul 25 Pierre Sujobert 26 Margot Robles 27 Raouf Ben Abdelali 28 Olivier Kosmider 29 Laurane Cottin 1, 2, 3 Lydia Roy 30, 31 Ivan Sloma 32, 33 Fabienne Vacheret 34 Mathieu Wemeau 35 Pascal Mossuz 36 Borhane Slama 37 Vincent Cussac 38 Guillaume Denis 39 Anouk Walter-Petrich 40 Barbara Burroni 41 Nathalie Jézéquel 7 Stéphane Giraudier 5, 6 Eric Lippert 7 Gérard Socié 42 Jean-Jacques Kiladjian 43, 5 Valérie Ugo 1, 2, 3 
1 CRCINA-ÉQUIPE 7 - Innate Immunity and Immunotherapy
CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
20 CRCINA-ÉQUIPE 10 - Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma
CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
24 Service de Cancérologie Biologique [CHU Poitiers]
CHU Poitiers - Centre hospitalier universitaire de Poitiers
40 CRESS - U1153 - Equipe 2 : ECSTRA - Epidémiologie Clinique, STatistique, pour la Recherche en Santé
CRESS (U1153 / UMR_A_1125 / UMR_S_1153) - Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité
Abstract : We aimed to study the prognostic impact of the mutational landscape in primary and secondary myelofibrosis. The study included 479 patients with myelofibrosis recruited from 24 French Intergroup of Myeloproliferative Neoplasms (FIM) centers. The molecular landscape was studied by high-throughput sequencing of 77 genes. A Bayesian network allowed the identification of genomic groups whose prognostic impact was studied in a multistate model considering transitions from the 3 conditions: myelofibrosis, acute leukemia, and death. Results were validated using an independent, previously published cohort (n 5 276). Four genomic groups were identified: patients with TP53 mutation; patients with $1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS, or KRAS (highrisk group); patients with ASXL1-only mutation (ie, no associated mutation in TP53 or highrisk genes); and other patients. A multistate model found that both TP53 and high-risk groups were associated with leukemic transformation (hazard ratios [HRs] [95% confidence interval], 8.68 [3.32-22.73] and 3.24 [1.58-6.64], respectively) and death from myelofibrosis (HRs, 3.03 [1.66-5.56] and 1.77 [1.18-2.67], respectively). ASXL1-only mutations had no prognostic value that was confirmed in the validation cohort. However, ASXL1 mutations conferred a worse prognosis when associated with a mutation in TP53 or high-risk genes. This study provides a new definition of adverse mutations in myelofibrosis with the addition of TP53, CBL, NRAS, KRAS, and U2AF1 to previously described genes. Furthermore, our results argue that ASXL1 mutations alone cannot be considered detrimental.
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Submitted on : Thursday, April 1, 2021 - 11:00:12 AM
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Damien Luque Paz, Jeremie Riou, Emmanuelle Verger, Bruno Cassinat, Aurélie Chauveau, et al.. Genomic analysis of primary and secondary myelofibrosis redefines the prognostic impact of ASXL1 mutations: a FIM study. Blood Advances, The American Society of Hematology, 2021, 5, pp.1442 - 1451. ⟨10.1182/bloodadvances.2020003444⟩. ⟨inserm-03187575⟩



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