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

dc.contributor.author

Mugoni, Vera

dc.contributor.author

Panella, Riccardo

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Cheloni, Giulia

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Chen, Ming

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Pozdnyakova, Olga

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Stroopinsky, Dina

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Guarnerio, Jlenia

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Monteleone, Emanuele

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Lee, Jonathan David

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Mendez, Lourdes

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Menon, Archita Venugopal

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Aster, Jon Christopher

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Lane, Andrew A

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Stone, Richard Maury

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Galinsky, Ilene

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Zamora, José Cervera

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Lo-Coco, Francesco

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Bhasin, Manoj Kumar

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Avigan, David

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Longo, Letizia

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Clohessy, John Gerard

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Pandolfi, Pier Paolo

dc.date.accessioned

2021-10-20T12:25:21Z

dc.date.available

2021-10-20T12:25:21Z

dc.date.issued

2019-06

dc.date.updated

2021-10-20T12:25:19Z

dc.description.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.

dc.identifier

10.1038/s41422-019-0162-7

dc.identifier.issn

1001-0602

dc.identifier.issn

1748-7838

dc.identifier.uri

https://hdl.handle.net/10161/23927

dc.language

eng

dc.publisher

Springer Science and Business Media LLC

dc.relation.ispartof

Cell research

dc.relation.isversionof

10.1038/s41422-019-0162-7

dc.subject

U937 Cells

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Tumor Cells, Cultured

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Animals

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Mice, Inbred C57BL

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Mice, Transgenic

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Humans

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Mice

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Leukemia, Promyelocytic, Acute

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Neoplasms, Experimental

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Disease Models, Animal

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Tretinoin

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Isocitrate Dehydrogenase

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Antineoplastic Combined Chemotherapy Protocols

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Mutation

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Leukemia, Myeloid, Acute

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Arsenic Trioxide

dc.title

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

dc.type

Journal article

duke.contributor.orcid

Chen, Ming|0000-0002-3470-1062

pubs.begin-page

446

pubs.end-page

459

pubs.issue

6

pubs.organisational-group

School of Medicine

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Duke Cancer Institute

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Pathology

pubs.organisational-group

Duke

pubs.organisational-group

Institutes and Centers

pubs.organisational-group

Clinical Science Departments

pubs.publication-status

Published

pubs.volume

29

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