LAUSR

Cancer stem cells (CSC) maintain both undifferentiated self-renewing CSCs and differentiated, non-self-renewing non-CSCs through cellular division. However, molecular mechanisms that maintain self-renewal in CSCs versus non-CSCs are not yet clear. Here, we report that in a transgenic mouse model of MYC-induced T cell leukemia, MYC maintains self-renewal in Sca1+ CSCs versus Sca-1- non-CSCs. MYC preferentially bound to the promoter and activated HIF-2α in Sca-1+ cells only. Further, the reprogramming factors Nanog and Sox2 facilitated MYC regulation of HIF-2α in Sca-1+ versus Sca-1- cells. Reduced expression of HIF-2α inhibited the self-renewal of Sca-1+ cells; this effect was blocked through suppression of reactive oxygen species (ROS) by N-acetyl cysteine (NAC) or the knock down of p53, Nanog or Sox2. Similar results were seen in ABCG2+ CSCs versus ABCG2- non-CSCs from primary human T cell lymphoma. Thus, MYC maintains self-renewal exclusively in CSCs by selectively binding to the promoter and activating the HIF-2α stemness pathway. Identification of this stemness pathway as a unique CSC determinant may have significant therapeutic implications.