Genetic characterization of ABT-199 sensitivity in human AML.
Leukemia
; 34(1): 63-74, 2020 01.
Article
in En
| MEDLINE
| ID: mdl-31300747
ABSTRACT
Acute myeloid leukemias (AML) with mutations in the NPM1 gene (NPM1c+) represent a large AML subgroup with varying response to conventional treatment, highlighting the need to develop targeted therapeutic strategies for this disease. We screened a library of clinical drugs on a cohort of primary human AML specimens and identified the BCL2 inhibitor ABT-199 as a selective agent against NPM1c+ AML. Mutational analysis of ABT-199-sensitive and -resistant specimens identified mutations in NPM1, RAD21, and IDH1/IDH2 as predictors of ABT-199 sensitivity. Comparative transcriptome analysis further uncovered BCL2A1 as a potential mediator of ABT-199 resistance in AML. In line with our observation that RAD21 mutation confers sensitivity to ABT-199, we provide functional evidence that reducing RAD21 levels can sensitize AML cells to BCL2 inhibition. Moreover, we demonstrate that ABT-199 is able to produce selective anti-AML activity in vivo toward AML with mutations associated with compound sensitivity in PDX models. Overall, this study delineates the contribution of several genetic events to the response to ABT-199 and provides a rationale for the development of targeted therapies for NPM1c+ AML.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Sulfonamides
/
Leukemia, Myeloid, Acute
/
Minor Histocompatibility Antigens
/
Drug Resistance, Neoplasm
/
Bridged Bicyclo Compounds, Heterocyclic
/
Proto-Oncogene Proteins c-bcl-2
/
Antineoplastic Agents
Type of study:
Diagnostic_studies
/
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Leukemia
Journal subject:
HEMATOLOGIA
/
NEOPLASIAS
Year:
2020
Document type:
Article
Affiliation country:
Canada