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

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 cyto-genetically normal AML, we propose that the circuit is functionally important in specific AML contexts. Katsumura et al. uncover a signaling mechanism that amplifies GATA-2 activity at select target genes in acute myeloid leukemia cells. Expression of GATA-2 target genes encoding the chemokine CXCL2 and cytokine IL-1β correlates with GATA-2 expression in a subtype of human AML, and high GATA-2/CXCL2 expression predicts poor prognosis.

主调控转录因子GATA - 2触发造血干细胞和祖细胞的产生。GATA2单倍体不足与骨髓增生异常综合征（MDS）和急性髓系白血病（AML）有关，并且GATA2过表达预示着AML预后不良。然而，介导发病机制的依赖于GATA - 2的基因网络的组成成分尚不清楚。我们描述了一种依赖于p38的机制，该机制使GATA - 2磷酸化并增加GATA - 2靶基因的激活。我们证明这种机制在AML细胞中建立了一个促进生长的趋化因子/细胞因子回路。p38/ERK依赖的GATA - 2磷酸化促进了GATA2转录的正反馈调节以及包括IL1B和CXCL2在内的靶基因的表达。IL - 1β和CXCL2增强了GATA - 2的磷酸化，这增加了GATA - 2介导的转录激活。p38/ERK - GATA - 2通过CXCL2的诱导刺激AML细胞增殖。由于在AML - M5中GATA2 mRNA与IL1B和CXCL2 mRNAs相关，并且这些基因的高表达预示着细胞遗传学正常的AML预后不良，我们提出该回路在特定的AML环境中具有重要的功能。 Katsumura等人揭示了一种在急性髓系白血病细胞中特定靶基因上放大GATA - 2活性的信号传导机制。在人类AML的一个亚型中，编码趋化因子CXCL2和细胞因子IL - 1β的GATA - 2靶基因的表达与GATA - 2的表达相关，并且高GATA - 2/CXCL2表达预示着预后不良。