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Dual origin of relapses in retinoic-acid resistant acute promyelocytic leukemia.
- Source :
-
Nature communications [Nat Commun] 2018 May 24; Vol. 9 (1), pp. 2047. Date of Electronic Publication: 2018 May 24. - Publication Year :
- 2018
-
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.
- Subjects :
- 5'-Nucleotidase genetics
5'-Nucleotidase metabolism
Animals
Humans
Leukemia, Promyelocytic, Acute metabolism
Male
Mice
Mutation
Promyelocytic Leukemia Protein genetics
Promyelocytic Leukemia Protein metabolism
Recurrence
Retinoic Acid Receptor alpha genetics
Retinoic Acid Receptor alpha metabolism
fms-Like Tyrosine Kinase 3 genetics
fms-Like Tyrosine Kinase 3 metabolism
Antineoplastic Agents administration & dosage
Arsenic Trioxide administration & dosage
Drug Resistance, Neoplasm
Leukemia, Promyelocytic, Acute drug therapy
Leukemia, Promyelocytic, Acute genetics
Tretinoin administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 29795382
- Full Text :
- https://doi.org/10.1038/s41467-018-04384-5