Journal Article

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

George, Derek, O’Carroll, Donal, De Pace, Azzura L., Guitart, Amelie V., van de Lagemaat, Louie N., Saffoon, Nadia, Arndt, Christine, Allen, Lewis, Dembitz, Vilma, Kranc, Kamil R., Holt-Martyn, James P., Kabayama, Yuka, Brewitz, Lennart, Bowen, Matthew, Tumber, Anthony, Atwal, Samanpreet, So, Chi Wai Eric, Corner, Thomas, Wang, Lydia M., Durko, Jozef, Schwaller, Juerg, Lawson, Hannah, Gallipoli, Paolo, Dubusse, Louis, Salah, Eidarus, Fung, Tsz Kan, Schofield, Christopher J., Bellani, Aarushi

2024

Overview

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.

• Publisher: Nature Publishing Group,Nature Research,Nature Publishing Group US
• Subject: Animals / Apoptosis - drug effects / Bridged Bicyclo Compounds, Heterocyclic / Cell Line, Tumor / Disease / Disease Progression / Genotype & phenotype / Hematology / Human health and pathology / Humans / Hypoxia / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors / Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - metabolism / Life Sciences / Medical prognosis / Membrane Proteins - genetics / Membrane Proteins - metabolism / Mice / Prolyl-Hydroxylase Inhibitors - pharmacology / Prolyl-Hydroxylase Inhibitors - therapeutic use / Protein Stability - drug effects / Proto-Oncogene Proteins - metabolism / Proto-Oncogene Proteins c-bcl-2 - metabolism / Software / Sulfonamides - pharmacology / Sulfonamides - therapeutic use / Transplants & implants