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Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy
Vera Mugoni1, Riccardo Panella1, Giulia Cheloni1
1Cancer 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.
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.
Insights
Targeting isocitrate dehydrogenase (IDH) mutations in acute myeloid leukemia (AML) is promising. This study reveals vulnerabilities in IDH-mutant leukemia, identifying a synergistic therapy combination for improved treatment outcomes.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Targeted therapies for human leukemia show efficacy but often face resistance.
- Isocitrate dehydrogenase (IDH) mutations occur in approximately 20% of acute myeloid leukemia (AML) cases, with targeted therapies under development.
- Understanding leukemia evolution and identifying persistent vulnerabilities is crucial for overcoming resistance.
Purpose of the Study:
- To characterize the evolution of leukemia from mutant IDH2 (mIDH2)-dependence to independence.
- To identify targetable vulnerabilities in mIDH2 leukemia that persist throughout disease progression.
- To explore novel therapeutic strategies for mIDH2-mutated AML.
Main Methods:
- Characterization of leukemia evolution from mIDH2-dependent to independent states.
- Mechanistic investigation of oxidative stress, 1-carbon metabolism, and glutathione levels.
- Analysis of LSD1 inhibition, PIN1 levels, and all-trans retinoic acid (ATRA) signaling.
- Assessment of therapeutic efficacy using mouse and human mIDH1/2 leukemic models.
Main Results:
- mIDH2 leukemia exhibits metastable vulnerabilities related to oxidative/genotoxic stress and suppressed ATRA signaling.
- Increased 1-carbon metabolism and glutathione levels do not fully mitigate stress in mIDH2 leukemia.
- Inhibition of LSD1 and increased PIN1 levels contribute to suppressed ATRA signaling.
- The combination of ATRA and arsenic trioxide (ATO) demonstrates powerful synergy and efficacy in preclinical models.
Conclusions:
- mIDH2 leukemia harbors distinct vulnerabilities at the GSH/ROS and PIN1/LSD1 nodes.
- The combination of ATRA and ATO effectively targets these vulnerabilities, showing significant therapeutic potential.
- Findings support the development of targeted, APL-like combinatorial therapies for IDH-mutated AML.
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