IntroductionThe hypoxia-inducible factor (HIF) pathway plays a protective role in regulating genes that mitigate the effects of low oxygen tension. Under normoxic conditions, oxygen-sensitive HIF-␣ isoforms are rendered inactive via proline hydroxylation by HIF-specific prolyl hydroxylases (HIF-PHs), which lead to binding of von HippelLindau protein and targeted degradation through the ubiquitinproteasome pathway. Under hypoxic conditions, where less oxygen substrate is available for proline hydroxylation by HIF-PHs, HIF-␣ isoforms are stabilized, heterodimerize with HIF-␤, and translocate to the nucleus where they bind to hypoxia-responsive element (HRE) motifs. [1][2][3] In cooperation with other transcriptional coactivators, HIF induces transcription of genes that ameliorate the effects of hypoxia, including EPO and its receptor, transferrin and its receptor, glucose transporters and glycolytic enzymes, and vascular endothelial growth factor (VEGF). 4 A relationship between fetal hemoglobin (HbF) levels and hypoxia has been reported for nearly half a century: increased HbF levels are associated with intrauterine hypoxia, 5 maternal smoking, 6 postnatal hypoxemia from congenital heart disease, 7,8 and anemia of prematurity. 9 Additionally, infants born at high altitude demonstrate enhanced erythropoiesis and elevated HbF levels compared with infants born at sea level. 10 Evidence for postnatal induction of HbF through a hypoxia pathway also exists in several species. Camelids adapt to hypoxia through increased fetal hemoglobin levels, with adult alpacas demonstrating HbF levels of 55% at high altitude. 11 In young baboons, significant increases in HbF levels occurred after phenylhydrazine induced hemolysis or hypobaric hypoxia. 12 While the magnitude of the HbF response may be genetically determined, 13 HbF levels could be maintained longterm by continued erythropoietic stress. 14 Indeed, a relationship between the HIF pathway and HbF expression has been proposed recently, and putative HIF-binding sites have been described in the locus control region of the globin gene cluster. 15 Thus modulating HIF-␣, the critical and labile subunit(s) in the HIF pathway orchestrating the response to hypoxia, represents a new direction to investigate for HbF induction.Stabilization of HIF-␣ through inhibition of HIF-PHs may have therapeutic potential in the treatment of the ␤-hemoglobinopathies. For example, the hypoxic environment during fetal development is protective for individuals with sickle cell anemia; however, following the transition to normoxia at birth, fetal hemoglobin levels fall with a gradual replacement of the ␥-globin chain by the abnormal ␤-globin chain, rendering the pathologic hemoglobin (Hb) tetramer prone to polymerization upon deoxygenation. The polymerized Hb leads to impaired deformability and sickling of red blood cells, which lodge in end arterioles, producing the classic and most prominent feature of the disorder, repeated vasoocclusive crises. Individuals who coinherit mutations resulting in her...

Nonmyeloablative parenteral busulfan produced transient myelosuppressive effects, clinically relevant levels of engraftment, and an extended time window for HSC infusion in murine hosts.