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.
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.
Stem Cell Biology Group, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.
C E
CE
Forristal
Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.|School of Pharmacy and Medical Science, Division of Health Sciences, University of South Australia, Adelaide, South Australia, Australia.
A L
AL
Brown
Stem Cell Biology Group, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.
F M
FM
Helwani
Cancer and Stem Cells Group, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.
I G
IG
Winkler
Stem Cell Biology Group, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.
B
B
Nowlan
Cancer and Stem Cells Group, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.
V
V
Barbier
Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.|School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
R J
RJ
Powell
Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.
G A
GA
Engler
Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.
S M
SM
Diakiw
Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.|School of Medical Sciences, Faculty of Health Science, University of Adelaide, Adelaide, South Australia, Australia.|South Australian Health and Medical Research Institute, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
A C W
AC
Zannettino
Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.|School of Medical Sciences, Faculty of Health Science, University of Adelaide, Adelaide, South Australia, Australia.
S
S
Martin
Cancer and Stem Cells Group, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.
D
D
Pattabiraman
Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.|School of Pharmacy and Medical Science, Division of Health Sciences, University of South Australia, Adelaide, South Australia, Australia.
R J
RJ
D'Andrea
Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.|School of Medical Sciences, Faculty of Health Science, University of Adelaide, Adelaide, South Australia, Australia.
I D
ID
Lewis
Stem Cell Biology Group, Mater Research Institute-University of Queensland, Woolloongabba, Queensland, Australia.|School of Medicine, University of Queensland, Herston, Queensland, Australia.
J P
JP
Levesque
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015687:Cell Hypoxia; D002478:Cells, Cultured; D015331:Cohort Studies; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D008223:Lymphoma / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D055815:Young Adult; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1