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

Vera Mugoni, Riccardo Panella, Giulia Cheloni, Ming Chen, Olga Pozdnyakova, Dina Stroopinsky, Jlenia Guarnerio, Emanuele Monteleone, Jonathan David Lee, Lourdes Mendez, Archita Venugopal Menon, Jon Christopher Aster, Andrew A. Lane, Richard Maury Stone, Ilene Galinsky, José Cervera Zamora, Francesco Lo-Coco, Manoj Kumar Bhasin, David Avigan, Letizia LongoJohn Gerard Clohessy, Pier Paolo Pandolfi

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalCell Research
DOIs
Publication statusPublished - Jan 1 2019

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Leukemia
Tretinoin
Therapeutics
DNA Damage
Glutathione
Oxidative Stress
Carbon
Maintenance
Enzymes
arsenic trioxide

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Mugoni, V., Panella, R., Cheloni, G., Chen, M., Pozdnyakova, O., Stroopinsky, D., ... Pandolfi, P. P. (2019). Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy. Cell Research. https://doi.org/10.1038/s41422-019-0162-7

Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy. / Mugoni, Vera; Panella, Riccardo; Cheloni, Giulia; Chen, Ming; Pozdnyakova, Olga; Stroopinsky, Dina; Guarnerio, Jlenia; Monteleone, Emanuele; Lee, Jonathan David; Mendez, Lourdes; Menon, Archita Venugopal; Aster, Jon Christopher; Lane, Andrew A.; Stone, Richard Maury; Galinsky, Ilene; Zamora, José Cervera; Lo-Coco, Francesco; Bhasin, Manoj Kumar; Avigan, David; Longo, Letizia; Clohessy, John Gerard; Pandolfi, Pier Paolo.

In: Cell Research, 01.01.2019.

Research output: Contribution to journalArticle

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, Stone, RM, Galinsky, I, Zamora, JC, Lo-Coco, F, Bhasin, MK, Avigan, D, Longo, L, Clohessy, JG & Pandolfi, PP 2019, 'Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy', Cell Research. https://doi.org/10.1038/s41422-019-0162-7
Mugoni, Vera ; Panella, Riccardo ; Cheloni, Giulia ; Chen, Ming ; Pozdnyakova, Olga ; Stroopinsky, Dina ; Guarnerio, Jlenia ; Monteleone, Emanuele ; Lee, Jonathan David ; Mendez, Lourdes ; Menon, Archita Venugopal ; Aster, Jon Christopher ; Lane, Andrew A. ; Stone, Richard Maury ; Galinsky, Ilene ; Zamora, José Cervera ; Lo-Coco, Francesco ; Bhasin, Manoj Kumar ; Avigan, David ; Longo, Letizia ; Clohessy, John Gerard ; Pandolfi, Pier Paolo. / Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy. In: Cell Research. 2019.
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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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AU - Panella, Riccardo

AU - Cheloni, Giulia

AU - Chen, Ming

AU - Pozdnyakova, Olga

AU - Stroopinsky, Dina

AU - Guarnerio, Jlenia

AU - Monteleone, Emanuele

AU - Lee, Jonathan David

AU - Mendez, Lourdes

AU - Menon, Archita Venugopal

AU - Aster, Jon Christopher

AU - Lane, Andrew A.

AU - Stone, Richard Maury

AU - Galinsky, Ilene

AU - Zamora, José Cervera

AU - Lo-Coco, Francesco

AU - Bhasin, Manoj Kumar

AU - Avigan, David

AU - Longo, Letizia

AU - Clohessy, John Gerard

AU - Pandolfi, Pier Paolo

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N2 - 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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