Research Papers:

Hypoxia inducible factor-1α regulates a pro-invasive phenotype in acute monocytic leukemia

Jessica Migliavacca, Stefano Percio, Roberta Valsecchi, Elisabetta Ferrero, Antonello Spinelli, Maurilio Ponzoni, Cristina Tresoldi, Linda Pattini, Rosa Bernardi and Nadia Coltella _

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Oncotarget. 2016; 7:53540-53557. https://doi.org/10.18632/oncotarget.10660

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Jessica Migliavacca1,2, Stefano Percio3, Roberta Valsecchi1,4, Elisabetta Ferrero1, Antonello Spinelli5, Maurilio Ponzoni2,6, Cristina Tresoldi7, Linda Pattini3, Rosa Bernardi1,*, Nadia Coltella1,*

1Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy

2Vita-Salute San Raffaele University School of Medicine, Milan, Italy

3Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy

4Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy

5Experimental Imaging Center, Preclinical Imaging Facility, IRCCS San Raffaele Scientific Institute, Milan, Italy

6Pathology Unit, IRCCS, San Raffaele Scientific Institute, Milan, Italy

7Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy

*These authors have contributed equally to this work

Correspondence to:

Nadia Coltella, email: coltella.nadia@hsr.it

Rosa Bernardi, email: bernardi.rosa@hsr.it

Keywords: acute monocytic leukemia, HIF-1α, motility, invasion, self-renewal

Received: February 15, 2016     Accepted: July 07, 2016     Published: July 18, 2016


Hypoxia inducible transcription factors (HIFs) are the main regulators of adaptive responses to hypoxia and are often activated in solid tumors, but their role in leukemia is less clear. In acute myeloid leukemia (AML), in particular, controversial new findings indicate that HIF-1α can act either as an oncogene or a tumor suppressor gene, and this may depend on the stage of leukemia development and/or the AML sub-type.

In this study, we find that HIF-1α promotes leukemia progression in the acute monocytic leukemia sub-type of AML through activation of an invasive phenotype. By applying a list of validated HIF-1α-target genes to different AML sub-types, we identified a HIF-1α signature that typifies acute monocytic leukemia when compared with all other AML sub-types. We validated expression of this signature in cell lines and primary cells from AML patients. Interestingly, this signature is enriched for genes that control cell motility at different levels. As a consequence, inhibiting HIF-1α impaired leukemia cell migration, chemotaxis, invasion and transendothelial migration in vitro, and this resulted in impaired bone marrow homing and leukemia progression in vivo. Our data suggest that in acute monocytic leukemia an active HIF-1α-dependent pro-invasive pathway mediates the ability of leukemic cells to migrate and invade extramedullary sites and may be targeted to reduce leukemia dissemination.

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