Summary Acute myeloid leukemia (AML) is an aggressive clonal disorder of hematopoietic stem cells (HSCs) and primitive progenitors that blocks their myeloid differentiation, generating self-renewing leukemic stem cells (LSCs). Here, we show that the mRNA m 6 A reader YTHDF2 is overexpressed in a broad spectrum of human AML and is required for disease initiation as well as propagation in mouse and human AML. YTHDF2 decreases the half-life of diverse m 6 A transcripts that contribute to the overall integrity of LSC function, including the tumor necrosis factor receptor Tnfrsf2 , whose upregulation in Ythdf2 -deficient LSCs primes cells for apoptosis. Intriguingly, YTHDF2 is not essential for normal HSC function, with YTHDF2 deficiency actually enhancing HSC activity. Thus, we identify YTHDF2 as a unique therapeutic target whose inhibition selectively targets LSCs while promoting HSC expansion.

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