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

• Published in: EMBO molecular medicine Vol. 6; no. 5; pp. 640 - 650
• Main Authors: Coltella, Nadia, Percio, Stefano, Valsecchi, Roberta, Cuttano, Roberto, Guarnerio, Jlenia, Ponzoni, Maurilio, Pandolfi, Pier Paolo, Melillo, Giovanni, Pattini, Linda, Bernardi, Rosa
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2014; EMBO Press; BlackWell Publishing Ltd; Springer Nature
• Subjects: acute promyelocytic leukemia; Acute promyeloid leukemia; Angiogenesis; Animal models; Animals; Binding sites; Bone marrow; Cancer; Cell adhesion & migration; Cell migration; Cell Physiological Phenomena; Cell self-renewal; Cooperation; Disease Models, Animal; EMBO03; EMBO18; Experiments; Fusion protein; Gene expression; Gene Expression Regulation; Humans; Hypothesis testing; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; hypoxia‐inducible transcription factor; Leukemia; Leukemia, Promyelocytic, Acute - physiopathology; leukemia‐initiating cells; Mice; mouse models; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pathogenesis; PML‐RARα; Promyelocytic Leukemia Protein; Promyeloid leukemia; Proteins; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - metabolism; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Recurrence; Research Article; Retinoic acid; Retinoic Acid Receptor alpha; Retinoic acid receptors; Stem cells; Transcription activation; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumors; mouse models; PML‐RARα; acute promyelocytic leukemia; hypoxia‐inducible transcription factor; leukemia‐initiating cells
• ISSN: 1757-4676; 1757-4684
• DOI: 10.1002/emmm.201303065

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. Graphical Abstract 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.