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

Katerndahl, Casey; Heltemes-Harris, Lynn; Willette, Mark; Henzler, Christine; Frietze, Seth; Yang, Rendong; Schjerven, Hilde; Silverstein, Kevin A.T.; Ramsey, Laura B.; Hubbard, Gregory K.; Wells, Andrew D.; Kuiper, Roland P.; Scheijen, Blanca; Leeuwen, Frank N. van; Müschen, Markus; Kornblau, Steven M.; Farrar, Michael A.

doi:10.1038/ni.3716

Cited by 71 publications

(77 citation statements)

References 53 publications

(70 reference statements)

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“…These are components of polycomb repressor complex 2 (PCR2), which promotes methylation of histone 3 at lysine 27 (FDR-adjusted P ≤ 0.05, Fisher’s exact test) ( Figure 8A , top, Supplemental Figure 9A , and Supplemental Table 4 ). STAT5 has recently been reported to oppose a network of transcription factors such as NF-κB and IKAROS in B cell acute lymphoblastic leukemia ( 52 ) and to interact with EZH2 ( 35 ). Furthermore, TOP2A expression has been previously linked to EZH2 expression in aggressive prostate cancer ( 53 ).…”

Section: Resultsmentioning

confidence: 99%

STAT5BN642H is a driver mutation for T cell neoplasia

Phạm

Maurer

Prchal-Murphy

et al. 2017

Journal of Clinical Investigation

107

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STAT5B is often mutated in hematopoietic malignancies. The most frequent STAT5B mutation, Asp642His (N642H), has been found in over 90 leukemia and lymphoma patients. Here, we used the Vav1 promoter to generate transgenic mouse models that expressed either human STAT5B or STAT5BN642H in the hematopoietic compartment. While STAT5B-expressing mice lacked a hematopoietic phenotype, the STAT5BN642H-expressing mice rapidly developed T cell neoplasms. Neoplasia manifested as transplantable CD8+ lymphoma or leukemia, indicating that the STAT5BN642H mutation drives cancer development. Persistent and enhanced levels of STAT5BN642H tyrosine phosphorylation in transformed CD8+ T cells led to profound changes in gene expression that were accompanied by alterations in DNA methylation at potential histone methyltransferase EZH2-binding sites. Aurora kinase genes were enriched in STAT5BN642H-expressing CD8+ T cells, which were exquisitely sensitive to JAK and Aurora kinase inhibitors. Together, our data suggest that JAK and Aurora kinase inhibitors should be further explored as potential therapeutics for lymphoma and leukemia patients with the STAT5BN642H mutation who respond poorly to conventional chemotherapy.

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Section: Resultsmentioning

confidence: 99%

STAT5BN642H is a driver mutation for T cell neoplasia

Phạm

Maurer

Prchal-Murphy

et al. 2017

Journal of Clinical Investigation

107

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“…For example, these studies have revealed the functional cooperation of STAT3 and IRF4 in IL-21 signaling (Kwon et al, 2009) and additional complex sites known as AP1-IRF4 composite elements (AICEs) that control IL-21 signaling in T cells , as well as genome-wide binding competition between GM-CSF-induced STAT5 and IL-21-induced STAT3 (Wan et al, 2013), opposing functions of STAT3 and STAT5 in Il17a and Il17f regulation , and competition between BLIMP1 and STAT5 (Poholek et al, 2016). Moreover, in the context of B cell acute lymphoblastic leukemia, STAT5 can antagonize the effects of NF-kB and Ikaros with high active STAT5 relative to these other factors, resulting in aggressive disease (Katerndahl et al, 2017).…”

Section: Evolutionary Considerationsmentioning

confidence: 99%

The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

2019

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The common cytokine receptor g chain, g c , is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding g c results in X-linked severe combined immunodeficiency in humans, and g c family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications.

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“…Of crucial note, integrating of overexpressed TFs in SE is commonly found in cancer. Particularly, in the patients with B-cell ALL, high ratios of active STAT5 to NF-κB or IKROS in SE also tend to strengthen seRNA expression, and show more aggressive disease phenotypes [70]. NF-κB is a critical TF for driving gene expression, which is involved with SE and seRNA formation [71].…”

Section: Oncogenic Serna Formationmentioning

confidence: 99%

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

Tan

Tang

2020

Mol Cancer

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seRNA is a noncoding RNA (ncRNA) transcribed from active super-enhancer (SE), through which SE exerts biological functions and participates in various physiological and pathological processes. seRNA recruits cofactor, RNA polymerase II and mediator to constitute and stabilize chromatin loop SE and promoter region, which regulates target genes transcription. In tumorigenesis, DNA insertion, deletion, translocation, focal amplification and carcinogen factor mediate oncogenic SE generation, meanwhile, oncogenic SE transcribes into tumor-related seRNA, termed as oncogenic seRNA. Oncogenic seRNA participates in tumorigenesis through activating various signal-pathways. The recent reports showed that oncogenic seRNA implicates in a widespread range of cytopathological processes in cancer progression including cell proliferation, apoptosis, autophagy, epithelial-mesenchymal transition, extracellular matrix stiffness and angiogenesis. In this article, we comprehensively summarized seRNA's characteristics and functions, and emphatically introduced inducible formation of oncogenic seRNA and its functional mechanisms. Lastly, some research strategies on oncogenic seRNA were introduced, and the perspectives on cancer therapy that targets oncogenic seRNA were also discussed.

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

Cited by 71 publications

References 53 publications

STAT5BN642H is a driver mutation for T cell neoplasia

STAT5BN642H is a driver mutation for T cell neoplasia

The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

Oncogenic seRNA functional activation: a novel mechanism of tumorigenesis

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