Concise review: genetic dissection of hypoxia signaling pathways in normal and leukemic stem cells.
Adult hematopoiesis depends on rare multipotent hematopoietic stem cells (HSCs) that self-renew and give rise to progenitor cells, which differentiate to all blood lineages. The strict regulation of the fine balance between self-renewal and differentiation is essential for normal hematopoiesis and suppression of leukemia development. HSCs and progenitor cells are commonly assumed to reside within the hypoxic BM microenvironment, however, there is no direct evidence supporting this notion. Nevertheless, HSCs and progenitors do exhibit a hypoxic profile and strongly express Hif-1α. Although hypoxia signaling pathways are thought to play important roles in adult HSC maintenance and leukemogenesis, the precise function of Hif-dependent signaling in HSCs remains to be uncovered. Here we discuss recent gain-of-function and loss-of-function studies that shed light on the complex roles of hypoxia-signaling pathways in HSCs and their niches in normal and malignant hematopoiesis. Importantly, we comment on the current and often contrasting interpretations of the role of Hif-dependent signaling in stem cell functions.
MRC Centre for Regenerative Medicine. University of Edinburgh, Edinburgh, United Kingdom; Paul O'Gorman Leukaemia Research Centre, University of Glasgow, Glasgow, United Kingdom; 3Klinik fuer Haematologie, Onkologie und Stammzelltransplantation, Universitaetsklinikum Aachen, Aachen, Germany.
Deniz
D
Gezer
Milica
M
Vukovic
Tomoyoshi
T
Soga
Patrick J
PJ
Pollard
Kamil R
KR
Kranc
D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit
Acute myeloid leukemia; Cited2; HIF-1; HIF-2; Hematological malignancies; Hematopoietic progenitors; Hematopoietic stem cells; Hypoxia