TY - JOUR
T1 - HIF factors cooperate with PML-RARα to promote acute promyelocytic leukemia progression and relapse
AU - Coltella, Nadia
AU - Percio, Stefano
AU - Valsecchi, Roberta
AU - Cuttano, Roberto
AU - Guarnerio, Jlenia
AU - Ponzoni, Maurilio
AU - Pandolfi, Pier Paolo
AU - Melillo, Giovanni
AU - Pattini, Linda
AU - Bernardi, Rosa
PY - 2014
Y1 - 2014
N2 - Acute 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).
AB - Acute 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).
KW - Acute promyelocytic leukemia
KW - Hypoxia-inducible transcription factor
KW - Leukemia-initiating cells
KW - Mouse models
KW - PML-RARα
UR - http://www.scopus.com/inward/record.url?scp=84899933855&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84899933855&partnerID=8YFLogxK
U2 - 10.1002/emmm.201303065
DO - 10.1002/emmm.201303065
M3 - Article
C2 - 24711541
AN - SCOPUS:84899933855
VL - 6
SP - 640
EP - 650
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 5
ER -