Portal de investigación
Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy
Fecha de publicación:
Autores de IIS La Fe
Participantes ajenos a IIS La Fe
- Mugoni, V
- Panella, R
- Cheloni, G
- Chen, M
- Pozdnyakova, O
- Stroopinsky, D
- Guarnerio, J
- Monteleone, E
- Lee, JD
- Mendez, L
- Menon, AV
- Aster, JC
- Lane, AA
- Stones, RM
- Galinsky, I
- Lo-Coco, F
- Bhasin, MK
- Avigan, D
- Longo, L
- Clohessy, JG
- Pandolfi, PP
Grupos
Abstract
Although targeted therapies have proven effective and even curative in human leukaemia, resistance often ensues. IDH enzymes are mutated in similar to 20% of human AML, with targeted therapies under clinical evaluation. We here characterize leukaemia evolution from mutant IDH2 (mIDH2)-dependence to independence identifying key targetable vulnerabilities of mIDH2 leukaemia that are retained during evolution and progression from early to late stages. Mechanistically, we find that mIDH2 leukaemia are metastable and vulnerable at two distinct levels. On the one hand, they are characterized by oxidative and genotoxic stress, in spite of increased 1-carbon metabolism and glutathione levels. On the other hand, mIDH2 leukaemia display inhibition of LSD1 and a resulting transcriptional signature of all-trans retinoic acid (ATRA) sensitization, in spite of a state of suppressed ATRA signalling due to increased levels of PIN1. We further identify GSH/ROS and PIN1/LSD1 as critical nodes for leukaemia maintenance and the combination of ATRA and arsenic trioxide (ATO) as a key therapeutic modality to target these vulnerabilities. Strikingly, we demonstrate that the combination of ATRA and ATO proves to be a powerfully synergistic and effective therapy in a number of mouse and human mIDH1/2 leukemic models. Thus, our findings pave the way towards the treatment of a sizable fraction of human AMLs through targeted APL-like combinatorial therapies.
Datos de la publicación
- ISSN/ISSNe:
- 1001-0602, 1748-7838
- Tipo:
- Article
- Páginas:
- 446-459
- PubMed:
- 31024166
- Factor de Impacto:
- 6,141 SCImago ℠
- Cuartil:
- Q1 SCImago ℠
CELL RESEARCH Nature Publishing Group
Citas Recibidas en Web of Science: 25
Documentos
- No hay documentos
Filiaciones
Cita
Mugoni V,Panella R,Cheloni G,Chen M,Pozdnyakova O,Stroopinsky D,Guarnerio J,Monteleone E,Lee JD,Mendez L,Menon AV,Aster JC,Lane AA,Stones RM,Galinsky I,ZAMORA JC,Lo F,Bhasin MK,Avigan D,Longo L,Clohessy JG,Pandolfi PP. Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy. Cell Res. 2019. 29. (6):p. 446-459. IF:20,507. (1).