The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia
Hannah Lawson, James P. Holt‐Martyn, Vilma Dembitz, Yuka Kabayama, Lydia M. Wang, Aarushi Bellani, Samanpreet Atwal, Nadia Saffoon, Jozef Durko, Louie N. van de Lagemaat, Azzura L. De Pace, Anthony Tumber, Thomas P. Corner, E. Salah, Christine Arndt, Lennart Brewitz, Matthew Bowen, Louis Dubusse, Derek George, Lewis Allen, Amélie V. Guitart, Tsz Kan Fung, Chi Wai Eric So, Juerg Schwaller, Paolo Gallipoli, Dónal O’Carroll, Christopher J. Schofield, Kamil R. Kranc
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.