HIF factors cooperate with PML-RARα to promote acute promyelocytic leukemia progression and relapse
Pandolfi, Pier Paolo
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CitationColtella, Nadia, Stefano Percio, Roberta Valsecchi, Roberto Cuttano, Jlenia Guarnerio, Maurilio Ponzoni, Pier Paolo Pandolfi, Giovanni Melillo, Linda Pattini, and Rosa Bernardi. 2014. “HIF factors cooperate with PML-RARα to promote acute promyelocytic leukemia progression and relapse.” EMBO Molecular Medicine 6 (5): 640-650. doi:10.1002/emmm.201303065. http://dx.doi.org/10.1002/emmm.201303065.
AbstractAcute promyelocytic leukemia (APL) is epitomized by the chromosomal translocation t(15;17) and the resulting oncogenic fusion protein PML-RARα. Although acting primarily as a transcriptional repressor, PML-RARα can also exert functions of transcriptional co-activation. Here, we find that PML-RARα stimulates transcription driven by HIF factors, which are critical regulators of adaptive responses to hypoxia and stem cell maintenance. Consistently, HIF-related gene signatures are upregulated in leukemic promyelocytes from APL patients compared to normal promyelocytes. Through in vitro and in vivo studies, we find that PML-RARα exploits a number of HIF-1α-regulated pro-leukemogenic functions that include cell migration, bone marrow (BM) neo-angiogenesis and self-renewal of APL blasts. Furthermore, HIF-1α levels increase upon treatment of APL cells with all-trans retinoic acid (ATRA). As a consequence, inhibiting HIF-1α in APL mouse models delays leukemia progression and exquisitely synergizes with ATRA to eliminate leukemia-initiating cells (LICs).
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