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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 hypoxia-inducible factor-2α ( HIF2α ) in Sca-1 + cells only. Furthermore, the reprogramming factors, Nanog and Sox2 , facilitated MYC regulation of HIF2α in Sca-1 + versus Sca-1 - cells. Reduced expression of HIF2α inhibited the self-renewal of Sca-1 + cells; this effect was blocked through suppression of ROS by N-acetyl cysteine or the knockdown 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 HIF2α stemness pathway. Identification of this stemness pathway as a unique CSC determinant may have significant therapeutic implications. SIGNIFICANCE: These findings show that the HIF2α stemness pathway maintains leukemic stem cells downstream of MYC in human and mouse T-cell leukemias. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4015/F1.large.jpg.

cancer research

MYCRegulates theHIF2αStemness Pathway viaNanogandSox2to Maintain Self-Renewal in Cancer Stem Cells versus Non-Stem Cancer Cells