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The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia

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Title: The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia
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
Contributors: Bellani, Aarushi, Kranc, Kamil
Source: Nat Cancer
Publisher Information: Springer Science and Business Media LLC, 2024.
Publication Year: 2024
Subject Terms: Myeloid, 0301 basic medicine, Sulfonamides / therapeutic use, Proto-Oncogene Proteins / metabolism, Hypoxia-Inducible Factor 1, alpha Subunit / metabolism, Apoptosis, Acute, alpha Subunit, Apoptosis / drug effects, Article, Cell Line, Hypoxia-Inducible Factor-Proline Dioxygenases, Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism, Bridged Bicyclo Compounds, Mice, 03 medical and health sciences, Proto-Oncogene Proteins, Cell Line, Tumor, Humans, Animals, Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors, Sulfonamides / pharmacology, Membrane Proteins / genetics, Sulfonamides, 0303 health sciences, Leukemia, Tumor, Prolyl-Hydroxylase Inhibitors / therapeutic use, Protein Stability, Heterocyclic, Protein Stability / drug effects, Prolyl-Hydroxylase Inhibitors / pharmacology, Membrane Proteins, Prolyl-Hydroxylase Inhibitors, Hypoxia-Inducible Factor 1, alpha Subunit, Bridged Bicyclo Compounds, Heterocyclic, Membrane Proteins / metabolism, 3. Good health, Leukemia, Myeloid, Acute, Proto-Oncogene Proteins c-bcl-2, Leukemia, Myeloid, Acute / metabolism, Disease Progression, Hypoxia-Inducible Factor 1, Leukemia, Myeloid, Acute / drug therapy, Proto-Oncogene Proteins c-bcl-2 / metabolism
Description: 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.
Document Type: Article
Other literature type
File Description: application/pdf; Print-Electronic
Language: English
ISSN: 2662-1347
DOI: 10.1038/s43018-024-00761-w
Access URL: https://pubmed.ncbi.nlm.nih.gov/38637657
Rights: CC BY
Accession Number: edsair.doi.dedup.....c3ffbd33d56d8858d6860493682c3c81
Database: OpenAIRE
Description
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.
ISSN:26621347
DOI:10.1038/s43018-024-00761-w