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Cell Res. 2019 Apr 25. doi: 10.1038/s41422-019-0162-7. [Epub ahead of print]

Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy.

Author information

1
Cancer Research Institute, Beth Israel Deaconess Cancer Center; Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
2
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
3
Division of Hematology and Hematologic Malignancies, Department of Medicine, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
4
Molecular Biotechnology Center and Department of Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza 52, 10126, Turin, Italy.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
6
Biobanco La Fe - Instituto de Investigation Sanitaria La Fe (IIS-LA FE), Avda. de Fernando Abril Martorell 106, 46026, Valencia, Spain.
7
Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
8
Neuro-Oncohematology Unit, Santa Lucia Foundation, Rome, Italy.
9
Division of IMBIO, Department of Medicine, BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.
10
Preclinical Murine Pharmacogenetics Core, Beth Israel Deaconess Cancer Center, Dana Farber/Harvard Cancer Center, Boston, USA.
11
Cancer Research Institute, Beth Israel Deaconess Cancer Center; Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA. ppandolf@bidmc.harvard.edu.

Abstract

Although targeted therapies have proven effective and even curative in human leukaemia, resistance often ensues. IDH enzymes are mutated in ~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.

PMID:
31024166
DOI:
10.1038/s41422-019-0162-7

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