<i>MYC</i> Regulates the <i>HIF2α</i> Stemness Pathway via <i>Nanog</i> and <i>Sox2</i> to Maintain Self-Renewal in Cancer Stem Cells versus Non-Stem Cancer Cells

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 (<i>HIF2α</i>) in Sca-1⁺ cells only. Furthermore, the reprogramming factors, <i>Nanog</i> and <i>Sox2</i>, facilitated MYC regulation of <i>HIF2α</i> in Sca-1⁺ versus Sca-1^- cells. Reduced expression of <i>HIF2α</i> 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, <i>Nanog</i>, or <i>Sox2</i>. 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 <i>HIF2α</i> stemness pathway. Identification of this stemness pathway as a unique CSC determinant may have significant therapeutic implications. SIGNIFICANCE: These findings show that the <i>HIF2α</i> 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.