American Association for Cancer Research
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00085472can182847-sup-208570_3_supp_5555082_psy87v.pdf (4.37 MB)

Supplementary Figures from MYC Regulates the HIF2α Stemness Pathway via Nanog and Sox2 to Maintain Self-Renewal in Cancer Stem Cells versus Non-Stem Cancer Cells

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posted on 2023-03-31, 02:44 authored by Bikul Das, Bidisha Pal, Rashmi Bhuyan, Hong Li, Anupam Sarma, Sukanya Gayan, Joyeeta Talukdar, Sorra Sandhya, Seema Bhuyan, Gayatri Gogoi, Arvin M. Gouw, Debabrat Baishya, Jason R. Gotlib, Amal C. Kataki, Dean W. Felsher

Supplemental figures provide additional supporting data to claim that MYC regulates the HIF-2a stemness pathway via Nanog and Sox2 to maintain self-renewal in CSCs versus non-CSCs

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ARTICLE ABSTRACT

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. These findings show that the HIF2α stemness pathway maintains leukemic stem cells downstream of MYC in human and mouse T-cell leukemias.

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