Identification of HIF2alpha as an important STAT5 target gene in human hematopoietic stem cells.

Abstract:

:The transcription factor signal transducer and activator of transcription 5 (STAT5) fulfills essential roles in self-renewal in mouse and human hematopoietic stem cells (HSCs), and its persistent activation contributes to leukemic transformation, although little molecular insight into the underlying mechanisms has been obtained. In the present study, we show that STAT5 can impose long-term expansion exclusively on human HSCs, not on progenitors. This was associated with an enhanced cobblestone formation under bone marrow stromal cells of STAT5-transduced HSCs. Hypoxia-induced factor 2α (HIF2α) was identified as a STAT5 target gene in HSCs, and chromatin immunoprecipitation studies revealed STAT5 binding to a site 344 base pairs upstream of the start codon of HIF2α. Lentiviral RNA interference (RNAi)-mediated down-modulation of HIF2α impaired STAT5-induced long-term expansion and HSC frequencies, whereas differentiation was not affected. Glucose uptake was elevated in STAT5-activated HSCs, and several genes associated with glucose metabolism were up-regulated by STAT5 in an HIF2α-dependent manner. Our studies indicate that pathways normally activated under hypoxia might be used by STAT5 under higher oxygen conditions to maintain and/or impose HSC self-renewal properties.

journal_name

Blood

journal_title

Blood

authors

Fatrai S,Wierenga AT,Daenen SM,Vellenga E,Schuringa JJ

doi

10.1182/blood-2010-08-303669

subject

Has Abstract

pub_date

2011-03-24 00:00:00

pages

3320-30

issue

12

eissn

0006-4971

issn

1528-0020

pii

blood-2010-08-303669

journal_volume

117

pub_type

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