HIF factors cooperate with PML‐RARα to promote acute promyelocytic leukemia progression and relapse

EMBO Molecular Medicine

Nadia Coltella⁴  Stefano Percio¹  Roberta Valsecchi⁴  Roberto Cuttano⁴  Jlenia Guarnerio⁴  Maurilio Ponzoni⁵  Pier Paolo Pandolfi³  Giovanni Melillo²  Linda Pattini¹ 

[1]Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy

[2]Science Applications International Corporation-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA

[3]Department of Medicine and Pathology, Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

[4]Division of Molecular Oncology, Leukemia Unit, San Raffaele Scientific Institute, Milan, Italy

[5]Pathology Unit, Leukemia Unit, San Raffaele Scientific Institute, Milan, Italy

关键词: acute promyelocytic leukemia;    hypoxia‐inducible transcription factor;    leukemia‐initiating cells;    mouse models;    PML‐RARα;   

DOI  :  10.1002/emmm.201303065

来源: Wiley

【 摘 要 】

Abstract

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).

Synopsis

PML-RARα cooperates with HIF-1α to activate a pro-leukemogenic program. Consequently, HIF-1α inhibition curbs leukemia progression and, in synergy with retinoic acid, eliminates leukemia-initiating cells.

• PML-RARα is a HIF-α transcriptional co-activator.
• HIF-dependent gene signatures are upregulated in APL leukemic promyelocytes.
• HIF-1α regulates cell migration, chemotaxis, neo-angiogenesis and self-renewal of leukemic blasts in acute promyelocytic leukemia.
• HIF-1α levels increase upon treatment of acute promyelocytic leukemia cells with all-trans retinoic acid.
• HIF-1α inhibition synergizes with all-trans retinoic acid to eliminate leukemia-initiating cells in acute promyelocytic leukemia.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.