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GATA Factor-Dependent Positive-Feedback Circuit in Acute Myeloid Leukemia Cells.

Abstract：

: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-1β 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 CXCL2 mRNAs 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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Katsumura KR,Ong IM,DeVilbiss AW,Sanalkumar R,Bresnick EH

doi

10.1016/j.celrep.2016.07.058

subject

Has Abstract

pub_date

2016-08-30 00:00:00

pages

2428-41

issue

9

issn

2211-1247

pii

S2211-1247(16)30989-5

journal_volume

16

pub_type

杂志文章

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