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.
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Acknowledgements
We thank all members of the Pandolfi laboratory for critical comments. Lauren Southwood and Elizabeth Stack for editing the manuscript. We are grateful to Markus Reschke, Akinobu Matsumoto, Nicole Pandell, Valerie Maymi, John Asara, John F. Daley and Zach Herbert for technical support with experiments. We are also thankful to Jacqueline Fung and Jesse M. Katon for their technical help and to Kun Ping Lu for support and reagents. V.M. was supported by EMBO Long Term post-doctoral fellowship (ALTF 1011–2014), European Commission (LTFCOFUND2013, GA-2013–609409) and by the Leukaemia and Lymphoma Society (Career Development Program, Grant number: 5437–16). R.P. was partially supported by Marie Curie Action Fellowship “Mobility Program for post graduated scientists in Life Sciences” (C.I.13001124001202512454). E.M. is supported by the Società Italiana di Biofisica e Biologia Molecolare (SIBBM). This work was supported in part by the Ludwig Center at Harvard and NIH/NCI grants R35CA197529. and R01CA142874 to P.P.P.
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P.P.P., V.M. and J.G.C. conceived the hypothesis, planned and designed the experiments and wrote the paper. L.L. managed the study. V.M. performed in vivo and in vitro experiments regarding mouse, human leukaemia primary cells and cell lines. V.M. engineered TF1 cell line for Pin1 overexpression or silencing. V.M and R.P. engineered the U937 and TF1 cell lines for the stable expression of the mutant variants R140Q of IDH2 and R132C of IDH1 and performed in vivo and in vitro experiments, real-time qRT-PCR and FACS analysis. M.C. performed western blot analyses on mouse and human leukaemia cells. G.C. performed colony assays on human mIDH AML. V.M and J.G.C. performed the pre-clinical trials, O.P. performed histopathological analyses, A.V.M., J.G.C., L.M., D.S., J.G., D.A., J.C.Z. and F.L. contributed to in vitro and in vivo experiments. J.C.A., A.L., R.M.S., I.G., D.S., D.A. and J.C.Z. provided human primary patient AML samples. E.M., J.D.L. and M.K.B. performed the bioinformatics analysis of the data.
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P.P.P. is a member of the Scientific Advisory Board of Agios Pharmaceuticals, Cambridge, MA. P.P.P., V.M., J.G.C. and M.C. have filed a U.S. Patent Application No. 62/593,761, entitled “ARSENIC TRIOXIDE AND RETINOIC ACID COMPOUNDS FOR TREATMENT OF IDH2-ASSOCIATED DISORDERS”, filed December 1, 2017. This application is still pending. The remaining authors declare no competing interests.
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Mugoni, V., Panella, R., Cheloni, G. et al. Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy. Cell Res 29, 446–459 (2019). https://doi.org/10.1038/s41422-019-0162-7
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DOI: https://doi.org/10.1038/s41422-019-0162-7
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