Key Points• Hif-2a-dependent signaling is dispensable for steady-state multilineage hematopoiesis.• Hif-2a is not essential for HSC self-renewal.Local hypoxia in hematopoietic stem cell (HSC) niches is thought to regulate HSC functions. Hypoxia-inducible factor-1 (Hif-1) and Hif-2 are key mediators of cellular responses to hypoxia. Although oxygen-regulated a-subunits of Hifs, namely Hif-1a and Hif-2a, are closely related, they play overlapping and also distinct functions in nonhematopoietic tissues. Although Hif-1a-deficient HSCs lose their activity on serial transplantation, the role for Hif-2a in cell-autonomous HSC maintenance remains unknown. Here, we demonstrate that constitutive or inducible hematopoiesis-specific Hif-2a deletion does not affect HSC numbers and steady-state hematopoiesis. Furthermore, using serial transplantations and 5-fluorouracil treatment, we demonstrate that HSCs do not require Hif-2a to self-renew and recover after hematopoietic injury. Finally, we show that Hif-1a deletion has no major impact on steady-state maintenance of Hif2a-deficient HSCs and their ability to repopulate primary recipients, indicating that Hif-1a expression does not account for normal behavior of Hif-2a-deficient HSCs. (Blood. 2013;122(10):1741-1745

Vukovic et al. report that Hif-1α and Hif-2α are not required for leukemia stem cell maintenance and AML propagation, but they act synergistically to suppress leukemia development in mice. Furthermore, knockout of HIF-2α or pharmacological inhibition of the HIF pathway in human AML cells has no impact on their survival and proliferation under hypoxic conditions.