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Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival.

ABSTRACT: The transcription factor STAT5 has a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we found that activation of STAT5 worked together with defects in signaling components of the precursor to the B cell antigen receptor (pre-BCR), including defects in BLNK, BTK, PKC?, NF-?B1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-?B and IKAROS by opposing regulation of shared target genes. Super-enhancers showed enrichment for STAT5 binding and were associated with an opposing network of transcription factors, including PAX5, EBF1, PU.1, IRF4 and IKAROS. Patients with a high ratio of active STAT5 to NF-?B or IKAROS had more-aggressive disease. Our studies indicate that an imbalance of two opposing transcriptional programs drives B-ALL and suggest that restoring the balance of these pathways might inhibit B-ALL.

SUBMITTER: Katerndahl CDS

PROVIDER: S-EPMC5540372 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival.

Katerndahl Casey D S CDS Heltemes-Harris Lynn M LM Willette Mark J L MJL Henzler Christine M CM Frietze Seth S Yang Rendong R Schjerven Hilde H Silverstein Kevin A T KAT Ramsey Laura B LB Hubbard Gregory G Wells Andrew D AD Kuiper Roland P RP Scheijen Blanca B van Leeuwen Frank N FN Müschen Markus M Kornblau Steven M SM Farrar Michael A MA

Nature immunology 20170403 6

The transcription factor STAT5 has a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we found that activation of STAT5 worked together with defects in signaling components of the precursor to the B cell antigen receptor (pre-BCR), including defects in BLNK, BTK, PKCβ, NF-κB1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κB and IKAROS by opposing regulation of shared target genes. Super-enhancers showed ...[more]

PMID: 28369050

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Project description:Flaviviruses are a diverse group of arthropod-borne viruses responsible for numerous significant public health threats; therefore, understanding the interactions between these viruses and the human immune response remains vital. West Nile virus (WNV) and Zika virus (ZIKV) infect human dendritic cells (DCs) and can block antiviral immune responses in DCs. Previously, we used mRNA sequencing and weighted gene coexpression network analysis (WGCNA) to define molecular signatures of antiviral DC responses following activation of innate immune signaling (RIG-I, MDA5, or type I interferon [IFN] signaling) or infection with WNV. Using this approach, we found that several genes involved in T cell cosignaling and antigen processing were not enriched in DCs during WNV infection. Using cis-regulatory sequence analysis, STAT5 was identified as a regulator of DC activation and immune responses downstream of innate immune signaling that was not activated during either WNV or ZIKV infection. Mechanistically, WNV and ZIKV actively blocked STAT5 phosphorylation downstream of RIG-I, IFN-β, and interleukin-4 (IL-4), but not granulocyte-macrophage colony-stimulating factor (GM-CSF), signaling. Unexpectedly, dengue virus serotypes 1 to 4 (DENV1 to DENV4) and the yellow fever 17D vaccine strain (YFV-17D) did not antagonize STAT5 phosphorylation. In contrast to WNV, ZIKV inhibited JAK1 and TYK2 phosphorylation following type I IFN treatment, suggesting divergent mechanisms used by these viruses to inhibit STAT5 activation. Combined, these findings identify STAT5 as a target of antagonism by specific pathogenic flaviviruses to subvert the immune response in infected DCs.IMPORTANCE Flaviviruses are a diverse group of insect-borne viruses responsible for numerous significant public health threats. Previously, we used a computational biology approach to define molecular signatures of antiviral DC responses following activation of innate immune signaling or infection with West Nile virus (WNV). In this work, we identify STAT5 as a regulator of DC activation and antiviral immune responses downstream of innate immune signaling that was not activated during either WNV or Zika virus (ZIKV) infection. WNV and ZIKV actively blocked STAT5 phosphorylation downstream of RIG-I, IFN-β, and IL-4, but not GM-CSF, signaling. However, other related flaviviruses, dengue virus serotypes 1 to 4 and the yellow fever 17D vaccine strain, did not antagonize STAT5 phosphorylation. Mechanistically, WNV and ZIKV showed differential inhibition of Jak kinases upstream of STAT5, suggesting divergent countermeasures to inhibit STAT5 activation. Combined, these findings identify STAT5 as a target of antagonism by specific pathogenic flaviviruses to subvert antiviral immune responses in human DCs.

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Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival.

Publications

Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival.

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