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Article Dans Une Revue Nature Communications Année : 2018

Dual origin of relapses in retinoic-acid resistant acute promyelocytic leukemia

Jacqueline Lehmann-Che
Cécile Bally
  • Fonction : Auteur
Eric Letouzé
Caroline Berthier
  • Fonction : Auteur
Hao Yuan
  • Fonction : Auteur
Florence Jollivet
  • Fonction : Auteur
Lionel Ades
Bruno Cassinat
Pierre Hirsch
Arnaud Pigneux
  • Fonction : Auteur
Marie-Joelle Mozziconacci
  • Fonction : Auteur
Scott Kogan
  • Fonction : Auteur
Pierre Fenaux
  • Fonction : Auteur

Résumé

Retinoic acid (RA) and arsenic target the t(15;17)(q24;q21) PML/RARA driver of acute promyelocytic leukemia (APL), their combination now curing over 95% patients. We report exome sequencing of 64 matched samples collected from patients at initial diagnosis, during remission, and following relapse after historical combined RA-chemotherapy treatments. A first subgroup presents a high incidence of additional oncogenic mutations disrupting key epigenetic or transcriptional regulators (primarily WT1) or activating MAPK signaling at diagnosis. Relapses retain these cooperating oncogenes and exhibit additional oncogenic alterations and/or mutations impeding therapy response (RARA, NT5C2). The second group primarily exhibits FLT3 activation at diagnosis, which is lost upon relapse together with most other passenger mutations, implying that these relapses derive from ancestral pre-leukemic PML/RARA-expressing cells that survived RA/chemotherapy. Accordingly, clonogenic activity of PML/RARA-immortalized progenitors ex vivo is only transiently affected by RA, but selectively abrogated by arsenic. Our studies stress the role of cooperating oncogenes in direct relapses and suggest that targeting pre-leukemic cells by arsenic contributes to its clinical efficacy.

Domaines

Cancer

Dates et versions

hal-03653853 , version 1 (28-04-2022)

Identifiants

Citer

Jacqueline Lehmann-Che, Cécile Bally, Eric Letouzé, Caroline Berthier, Hao Yuan, et al.. Dual origin of relapses in retinoic-acid resistant acute promyelocytic leukemia. Nature Communications, 2018, 9 (1), pp.2047. ⟨10.1038/s41467-018-04384-5⟩. ⟨hal-03653853⟩
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