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

Jacqueline Lehmann-Che,Pierre Hirsch,Eric Letouzé,Hugues De Thé,Cécile Bally,Arnaud Pigneux,Bruno Cassinat,Lionel Ades,Marie-Joelle Mozziconacci,Florence Jollivet,Pierre Fenaux,Caroline Berthier,Scott Kogan,Hao Yuan

doi:10.1038/s41467-018-04384-5

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.

Highlights

Retinoic acid (RA) and arsenic target the t(15;17)(q24;q21) PML/RARA driver of acute promyelocytic leukemia (APL), their combination curing over 95% patients
To define the pre-existing or acquired mutations associated with RA/ chemotherapy resistance, we performed whole-exome sequencing of diagnosis and relapse pairs from 23 patients recruited through the French Swiss Belgian APL group (GTLAP) trials
We found that many APLs that will undergo relapse are associated with the presence at diagnosis of a high prevalence of WT1 alteration as well as uncommon mutations affecting activators of MAP kinase pathway and/or other epigenetic regulators (Fig. 2), suggesting that these are responsible for therapy resistance[31]

Summary

Introduction

Retinoic acid (RA) and arsenic target the t(15;17)(q24;q21) PML/RARA driver of acute promyelocytic leukemia (APL), their combination curing over 95% patients. 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). WT1, KRAS, NRAS mutations, FLT3 activation, or Myc trisomy, which are common genetic events in many other subsets of acute myeloid leukemia (AML), may be observed in APL patients[9,10,11,12,13,14] These progression events, which occur late in APL or AML development, sharply accelerate PML/RARA-driven transformation in murine models[15,16,17]. We show that relapses are associated with the presence of potent PML/RARA cooperating oncogenes at diagnosis, or re-emergence of an ancestral pre-leukemic clone that survived targeted therapy with RA

Methods

Results

Conclusion