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

Abstract

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.

• Authors: Jacqueline Lehmann-Che, Cécile Bally, Eric Letouzé, Caroline Berthier, Hao Yuan, Florence Jollivet, Lionel Ades, Bruno Cassinat, Pierre Hirsch, Arnaud Pigneux, Marie-Joelle Mozziconacci, Scott Kogan, Pierre Fenaux, Hugues de Thé
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 2047 (05 24 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 29795382 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Promyelocytic Leukemia Protein
• RARA protein, human
• Retinoic Acid Receptor alpha
• PML protein, human
• Tretinoin
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3
• 5'-Nucleotidase
• NT5C2 protein, human
• Arsenic Trioxide

Topics

• 5'-Nucleotidase (genetics, metabolism)
• Animals
• Antineoplastic Agents (administration & dosage)
• Arsenic Trioxide (administration & dosage)
• Drug Resistance, Neoplasm
• Humans
• Leukemia, Promyelocytic, Acute (drug therapy, genetics, metabolism)
• Male
• Mice
• Mutation
• Promyelocytic Leukemia Protein (genetics, metabolism)
• Recurrence
• Retinoic Acid Receptor alpha (genetics, metabolism)
• Tretinoin (administration & dosage)
• fms-Like Tyrosine Kinase 3 (genetics, metabolism)