RESUMEN
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.
Asunto(s)
Progresión de la Enfermedad , Subunidad alfa del Factor 1 Inducible por Hipoxia , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Leucemia Mieloide Aguda , Inhibidores de Prolil-Hidroxilasa , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Humanos , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Inhibidores de Prolil-Hidroxilasa/farmacología , Inhibidores de Prolil-Hidroxilasa/uso terapéutico , Animales , Ratones , Apoptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Línea Celular Tumoral , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Estabilidad Proteica/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con PuentesRESUMEN
Hematopoietic stem cells (HSCs) reside at the apex of the hematopoietic differentiation hierarchy and sustain multilineage hematopoiesis. Here, we show that the transcriptional regulator CITED2 is essential for life-long HSC maintenance. While hematopoietic-specific Cited2 deletion has a minor impact on steady-state hematopoiesis, Cited2-deficient HSCs are severely depleted in young mice and fail to expand upon aging. Moreover, although they home normally to the bone marrow, they fail to reconstitute hematopoiesis upon transplantation. Mechanistically, CITED2 is required for expression of key HSC regulators, including GATA2, MCL-1, and PTEN. Hematopoietic-specific expression of anti-apoptotic MCL-1 partially rescues the Cited2-deficient HSC pool and restores their reconstitution potential. To interrogate the Cited2âPten pathway in HSCs, we generated Cited2;Pten compound heterozygous mice, which had a decreased number of HSCs that failed to reconstitute the HSC compartment. In addition, CITED2 represses multiple pathways whose elevated activity causes HSC exhaustion. Thus, CITED2 promotes pathways necessary for HSC maintenance and suppresses those detrimental to HSC integrity.