HIF factors cooperate with PML-RAR? to promote acute promyelocytic leukemia progression and relapse.

ABSTRACT: Acute promyelocytic leukemia (APL) is epitomized by the chromosomal translocation t(15;17) and the resulting oncogenic fusion protein PML-RAR?. Although acting primarily as a transcriptional repressor, PML-RAR? can also exert functions of transcriptional co-activation. Here, we find that PML-RAR? 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-RAR? exploits a number of HIF-1?-regulated pro-leukemogenic functions that include cell migration, bone marrow (BM) neo-angiogenesis and self-renewal of APL blasts. Furthermore, HIF-1? levels increase upon treatment of APL cells with all-trans retinoic acid (ATRA). As a consequence, inhibiting HIF-1? in APL mouse models delays leukemia progression and exquisitely synergizes with ATRA to eliminate leukemia-initiating cells (LICs).

SUBMITTER: Coltella N 

PROVIDER: S-EPMC4023886 | biostudies-other | 2014 May

REPOSITORIES: biostudies-other