Genomics

Dataset Information

0

Exome sequencing demonstrates a dual origin of relapses in retinoic-acid resistant acute promyelocytic leukemia.


ABSTRACT: Retinoic acid (RA) and arsenic target the PML/RARA driver of Acute Promyelocytic Leukemia (APL), their combination now curing over 95% patients. Here we report exome sequencing of 64 matched diagnosis/remission/relapses patients treated with historical RA/chemotherapy protocols. A first subgroup presents a high incidence of 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 relapses derive from 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.

PROVIDER: EGAS00001002893 | EGA |

REPOSITORIES: EGA

Similar Datasets

2020-05-26 | PXD012954 | Pride
2020-04-20 | GSE128529 | GEO
2020-04-20 | GSE128528 | GEO
2015-10-01 | GSE68844 | GEO
2010-03-23 | E-GEOD-18497 | biostudies-arrayexpress
2022-06-09 | GSE151837 | GEO
2016-06-01 | E-GEOD-65720 | biostudies-arrayexpress
2023-11-19 | GSE210190 | GEO
2010-03-10 | GSE18497 | GEO
2014-01-11 | GSE51723 | GEO