| First Author | Das B | Year | 2019 |
| Journal | Cancer Res | Volume | 79 |
| Issue | 16 | Pages | 4015-4025 |
| PubMed ID | 31266772 | Mgi Jnum | J:278952 |
| Mgi Id | MGI:6359552 | Doi | 10.1158/0008-5472.CAN-18-2847 |
| Citation | Das B, et al. (2019) MYC Regulates the HIF2alpha Stemness Pathway via Nanog and Sox2 to Maintain Self-Renewal in Cancer Stem Cells versus Non-Stem Cancer Cells. Cancer Res 79(16):4015-4025 |
| abstractText | 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-2alpha (HIF2alpha) in Sca-1(+) cells only. Furthermore, the reprogramming factors, Nanog and Sox2, facilitated MYC regulation of HIF2alpha in Sca-1(+) versus Sca-1(-) cells. Reduced expression of HIF2alpha 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 HIF2alpha stemness pathway. Identification of this stemness pathway as a unique CSC determinant may have significant therapeutic implications. SIGNIFICANCE: These findings show that the HIF2alpha 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. |
