HIF factors cooperate with PML‐RARα 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‐RARα. Although acting primarily as a transcriptional repressor, PML‐RARα can also exert functions of transcriptional co‐activation. Here, we find that PM...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2014-04-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/emmm.201303065 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850203461943033856 |
|---|---|
| author | Nadia Coltella Stefano Percio Roberta Valsecchi Roberto Cuttano Jlenia Guarnerio Maurilio Ponzoni Pier Paolo Pandolfi Giovanni Melillo Linda Pattini Rosa Bernardi |
| author_facet | Nadia Coltella Stefano Percio Roberta Valsecchi Roberto Cuttano Jlenia Guarnerio Maurilio Ponzoni Pier Paolo Pandolfi Giovanni Melillo Linda Pattini Rosa Bernardi |
| author_sort | Nadia Coltella |
| collection | DOAJ |
| description | 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). |
| format | Article |
| id | doaj-art-31a3e7fe7bc94b6796ee63b9a09c16e2 |
| institution | OA Journals |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2014-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-31a3e7fe7bc94b6796ee63b9a09c16e22025-08-20T02:11:30ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842014-04-016564065010.1002/emmm.201303065HIF factors cooperate with PML‐RARα to promote acute promyelocytic leukemia progression and relapseNadia Coltella0Stefano Percio1Roberta Valsecchi2Roberto Cuttano3Jlenia Guarnerio4Maurilio Ponzoni5Pier Paolo Pandolfi6Giovanni Melillo7Linda Pattini8Rosa Bernardi9Division of Molecular Oncology, Leukemia Unit, San Raffaele Scientific InstituteDepartment of Electronics, Information and Bioengineering, Politecnico di MilanoDivision of Molecular Oncology, Leukemia Unit, San Raffaele Scientific InstituteDivision of Molecular Oncology, Leukemia Unit, San Raffaele Scientific InstituteDivision of Molecular Oncology, Leukemia Unit, San Raffaele Scientific InstitutePathology Unit, Leukemia Unit, San Raffaele Scientific InstituteDepartment of Medicine and Pathology, Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical SchoolScience Applications International Corporation‐Frederick, Inc., Frederick National Laboratory for Cancer ResearchDepartment of Electronics, Information and Bioengineering, Politecnico di MilanoDivision of Molecular Oncology, Leukemia Unit, San Raffaele Scientific InstituteAbstract 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).https://doi.org/10.1002/emmm.201303065acute promyelocytic leukemiahypoxia‐inducible transcription factorleukemia‐initiating cellsmouse modelsPML‐RARα |
| spellingShingle | Nadia Coltella Stefano Percio Roberta Valsecchi Roberto Cuttano Jlenia Guarnerio Maurilio Ponzoni Pier Paolo Pandolfi Giovanni Melillo Linda Pattini Rosa Bernardi HIF factors cooperate with PML‐RARα to promote acute promyelocytic leukemia progression and relapse EMBO Molecular Medicine acute promyelocytic leukemia hypoxia‐inducible transcription factor leukemia‐initiating cells mouse models PML‐RARα |
| title | HIF factors cooperate with PML‐RARα to promote acute promyelocytic leukemia progression and relapse |
| title_full | HIF factors cooperate with PML‐RARα to promote acute promyelocytic leukemia progression and relapse |
| title_fullStr | HIF factors cooperate with PML‐RARα to promote acute promyelocytic leukemia progression and relapse |
| title_full_unstemmed | HIF factors cooperate with PML‐RARα to promote acute promyelocytic leukemia progression and relapse |
| title_short | HIF factors cooperate with PML‐RARα to promote acute promyelocytic leukemia progression and relapse |
| title_sort | hif factors cooperate with pml rarα to promote acute promyelocytic leukemia progression and relapse |
| topic | acute promyelocytic leukemia hypoxia‐inducible transcription factor leukemia‐initiating cells mouse models PML‐RARα |
| url | https://doi.org/10.1002/emmm.201303065 |
| work_keys_str_mv | AT nadiacoltella hiffactorscooperatewithpmlraratopromoteacutepromyelocyticleukemiaprogressionandrelapse AT stefanopercio hiffactorscooperatewithpmlraratopromoteacutepromyelocyticleukemiaprogressionandrelapse AT robertavalsecchi hiffactorscooperatewithpmlraratopromoteacutepromyelocyticleukemiaprogressionandrelapse AT robertocuttano hiffactorscooperatewithpmlraratopromoteacutepromyelocyticleukemiaprogressionandrelapse AT jleniaguarnerio hiffactorscooperatewithpmlraratopromoteacutepromyelocyticleukemiaprogressionandrelapse AT maurilioponzoni hiffactorscooperatewithpmlraratopromoteacutepromyelocyticleukemiaprogressionandrelapse AT pierpaolopandolfi hiffactorscooperatewithpmlraratopromoteacutepromyelocyticleukemiaprogressionandrelapse AT giovannimelillo hiffactorscooperatewithpmlraratopromoteacutepromyelocyticleukemiaprogressionandrelapse AT lindapattini hiffactorscooperatewithpmlraratopromoteacutepromyelocyticleukemiaprogressionandrelapse AT rosabernardi hiffactorscooperatewithpmlraratopromoteacutepromyelocyticleukemiaprogressionandrelapse |