The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia.
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ICR Authors
Authors
Lawson, H
Holt-Martyn, JP
Dembitz, V
Kabayama, Y
Wang, LM
Bellani, A
Atwal, S
Saffoon, N
Durko, J
van de Lagemaat, LN
De Pace, AL
Tumber, A
Corner, T
Salah, E
Arndt, C
Brewitz, L
Bowen, M
Dubusse, L
George, D
Allen, L
Guitart, AV
Fung, TK
So, CWE
Schwaller, J
Gallipoli, P
O'Carroll, D
Schofield, CJ
Kranc, KR
Holt-Martyn, JP
Dembitz, V
Kabayama, Y
Wang, LM
Bellani, A
Atwal, S
Saffoon, N
Durko, J
van de Lagemaat, LN
De Pace, AL
Tumber, A
Corner, T
Salah, E
Arndt, C
Brewitz, L
Bowen, M
Dubusse, L
George, D
Allen, L
Guitart, AV
Fung, TK
So, CWE
Schwaller, J
Gallipoli, P
O'Carroll, D
Schofield, CJ
Kranc, KR
Document Type
Journal Article
Date
2024-06-01
Date Accepted
2024-03-15
Abstract
Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax.
Citation
Nature Cancer, 2024, 5 (6), pp. 916 - 937
Source Title
Nature Cancer
Publisher
NATURE PORTFOLIO
ISSN
2662-1347
eISSN
2662-1347
2662-1347
2662-1347
Collections
Research Team
Haemato-Oncology