Hypoxia inducible factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML.

Abstract

Hypoxia-inducible factor (HIF)-1α accumulation promotes hematopoietic stem cells' quiescence and is necessary to maintain their self-renewal. However, the role of HIF-2α in hematopoietic cells is less clear. We investigated the role of HIF-2α in leukemia and lymphoma cells. HIF-2α expression was high in subsets of human and mouse leukemia and lymphoma cells, whereas it was low in normal bone marrow leukocytes. To investigate the role of HIF-2α, we transduced human HIF-2α cDNA in mouse syngeneic models of myeloid preleukemia and a transgenic model of B lymphoma. Ectopic expression of HIF-2α accelerated leukemia cell proliferation in vitro. Mice transplanted with cells transduced with HIF-2α died significantly faster of leukemia or B lymphoma than control mice transplanted with empty vector-transduced cells. Conversely, HIF-2α knockdown in human myeloid leukemia HL60 cells decreased proliferation in vitro and significantly prolonged animal survival following transplantation. In human acute myeloid leukemia (AML), HIF-2α mRNA was significantly elevated in several subsets such as the t(15;17), inv(16), complex karyotype and favorable cytogenetic groups. However, patients with high HIF-2α expression had a trend to higher disease-free survival in univariate analysis. The different effects of HIF-2α overexpression in mouse models of leukemia and human AML illustrates the complexity of this mutliclonal disease.

• Authors: C E Forristal, A L Brown, F M Helwani, I G Winkler, B Nowlan, V Barbier, R J Powell, G A Engler, S M Diakiw, A C W Zannettino, S Martin, D Pattabiraman, R J D'Andrea, I D Lewis, J P Levesque
• Journal: Leukemia (Leukemia) Vol. 29 Issue 10 Pg. 2075-85 (Oct 2015) ISSN: 1476-5551 [Electronic] England
• PMID: 25921247 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• RNA, Messenger
• endothelial PAS domain-containing protein 1

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Animals
• Basic Helix-Loop-Helix Transcription Factors (genetics, metabolism)
• Blotting, Western
• Cell Hypoxia
• Cells, Cultured
• Cohort Studies
• Disease Models, Animal
• Disease Progression
• Female
• Follow-Up Studies
• Hematopoietic Stem Cells (metabolism, pathology)
• Humans
• Immunoenzyme Techniques
• Leukemia, Myeloid, Acute (genetics, mortality, pathology)
• Lymphoma (genetics, mortality, pathology)
• Male
• Mice
• Mice, Transgenic
• Middle Aged
• Neoplasm Staging
• Prognosis
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Rate
• Young Adult