Journal
CELL REPORTS
Volume 16, Issue 9, Pages 2428-2441Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.07.058
Keywords
-
Categories
Funding
- NIH [DK68634]
- Midwest Athletes Against Childhood Cancer Organization
- Cancer Center Support Grant [P30 CA014520]
- Kanae Foundation for the Promotion of Medical Science
- American Heart Association Predoctoral Fellowship
- Cancer Center Support Grant from the Carbone Cancer Center [P30 CA014520]
- NIH National Center for Advancing Translational Sciences (NCATS) [UL1TR000427]
- Cancer Biology Predoctoral NIH Training Grant from the NIH [T32CA009135]
Ask authors/readers for more resources
The master regulatory transcription factor GATA-2 triggers hematopoietic stem and progenitor cell generation. GATA2 haploinsufficiency is implicated in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and GATA2 overexpression portends a poor prognosis for AML. However, the constituents of the GATA-2-dependent genetic network mediating pathogenesis are unknown. We described a p38-dependent mechanism that phosphorylates GATA-2 and increases GATA-2 target gene activation. We demonstrate that this mechanism establishes a growth-promoting chemokine/cytokine circuit in AML cells. p38/ERK-dependent GATA-2 phosphorylation facilitated positive autoregulation of GATA2 transcription and expression of target genes, including IL1B and CXCL2. IL-1 beta and CXCL2 enhanced GATA-2 phosphorylation, which increased GATA-2-mediated transcriptional activation. p38/ERK-GATA-2 stimulated AML cell proliferation via CXCL2 induction. As GATA2 mRNA correlated with IL1B and CXCL2mRNAs in AML-M5 and high expression of these genes predicted poor prognosis of cytogenetically normal AML, we propose that the circuit is functionally important in specific AML contexts.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available