Hypoxia has been reported to regulate both stem cell maintenance and differentiation. Wnt signaling is also a key regulator in stem cells. The recent discovery of functional cross-regulation between the Wnt pathway and HIF-1α/HIF-2α signaling further highlights the complexity of the role of hypoxia in the regulation of stem cells. In this report we reveal that human CML cell lines treated under hypoxic conditions increase the percentage of leukemia stem/initiating-like cells, as judged by surface marker expression, colony forming ability and quiescence. We demonstrate that differential usage of the Kat3 coactivators, CREBBP/Creb Binding Protein (CBP) and EP300 (p300) by catenin, with increased CBP/catenin signaling at the expense of p300/catenin signaling, is mechanistically correlated with the increase in the leukemia stem/initiating-like population. A specific small molecule inhibitor of CBP/catenin dependent transcription, ICG-001, can reverse these effects further demonstrating the critical involvement of CBP/catenin signaling in enhancing and maintaining the leukemia stem/initiating-like cell population under hypoxic conditions.