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STAT5BN642H is a driver mutation for T-cell neoplasia (RRBS)

ABSTRACT: The most frequent mutation in STAT5B is the Asp642His (N642H) mutation that was found in >90 leukemic/lymphoma patients. The development of novel treatment against STAT5BN642H has been hindered by the unavailability of a suitable model and the lack of the direct causal effect of STAT5BN642H on T-cell neoplasia development. We herein demonstrate that mice expressing human STAT5BN642H in the hematopoietic compartment rapidly develop leukemia/lymphoma. The disease is fully transplantable and characterized by the expansion of CD8+ T-cells. hSTAT5BN642H displays persistent and enhanced tyrosine phosphorylation upon cytokine stimulation. This leads to drastic changes in the gene expression profile accompanied by specific alterations in DNA methylation patterns that result in the acceleration of cell cycle progression. hSTAT5BN642H transcriptional activities in T-cell can be inhibited by inhibition of upstream kinases or transcriptional coregulaters, including JAKs, HDACs and BET Bromodomain containing protein. In particular, treatment with ruxolitinib, a JAK kinase inhibitor dramatically reduced tyrosine phosphorylation of hSTAT5BN642H resulting in decreased organ infiltration in vivo. We conclude that hSTAT5BN642H is sufficient to cause leukemia in vivo and JAK inhibitors are potential therapy for leukemic patients with the hSTAT5BN642H.

ORGANISM(S): Mus musculus

PROVIDER: GSE104557 | GEO | 2023/01/14

REPOSITORIES: GEO

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STAT5BN642H is a driver mutation for T-cell neoplasia (RNA-Seq)

Project description:The most frequent mutation in STAT5B is the Asp642His (N642H) mutation that was found in >90 leukemic/lymphoma patients. The development of novel treatment against STAT5BN642H has been hindered by the unavailability of a suitable model and the lack of the direct causal effect of STAT5BN642H on T-cell neoplasia development. We herein demonstrate that mice expressing human STAT5BN642H in the hematopoietic compartment rapidly develop leukemia/lymphoma. The disease is fully transplantable and characterized by the expansion of CD8+ T-cells. hSTAT5BN642H displays persistent and enhanced tyrosine phosphorylation upon cytokine stimulation. This leads to drastic changes in the gene expression profile accompanied by specific alterations in DNA methylation patterns that result in the acceleration of cell cycle progression. hSTAT5BN642H transcriptional activities in T-cell can be inhibited by inhibition of upstream kinases or transcriptional coregulaters, including JAKs, HDACs and BET Bromodomain containing protein. In particular, treatment with ruxolitinib, a JAK kinase inhibitor dramatically reduced tyrosine phosphorylation of hSTAT5BN642H resulting in decreased organ infiltration in vivo. We conclude that hSTAT5BN642H is sufficient to cause leukemia in vivo and JAK inhibitors are potential therapy for leukemic patients with the hSTAT5BN642H.

2020-02-24 | GSE93847 | GEO

Tyrosine phosphorylation of both STAT5A and STAT5B is necessary for maximal IL-2 signaling and its mitogenic action

Project description:STAT5 proteins are vital for lymphocyte development and function. Cytokine activation of STAT5A and STAT5B involves the tyrosine phosphorylation of a C-terminal tyrosine in each protein; however, the importance of STAT5 tyrosine phosphorylation in vivo has not been assessed. Here we generated Stat5a and Stat5b tyrosine mutant knockin mice and found they had greatly reduced CD8+ T-cell numbers. Morever, these cells exhibited profoundly diminished IL-2-induced proliferation, correlating with reduced IL-2- mediated induction of Myc, pRB, a range of cyclins and CDKs, and a G1àS phase- transition block. The mutant CD8+ T cells also exhibited decreased IL-2-mediated activation of pERK and pAKT, which can in part be attributed to diminished IL-2-induced expression of IL-2Rb and IL-2Rg. Our findings demonstrate that tyrosine phosphorylation of both STAT5A and STAT5B is essential for maximal IL-2 signaling, and our transcriptomic and proteomic analyses elucidate the molecular basis for the mitogenic effects of IL-2 on CD8+ T cells.

2024-05-10 | GSE247343 | GEO

Rajala_et_al_2013

Project description:Large lymphocytic leukemia (LGL) is a chronic clonal lymphoproliferative disorder, characterized by expansion of cytotoxic CD8+ T-cells or NK-cells. We compared gene expression of 3 LGL leukemia patients with STAT3 mutation (Patients 1, 2, and 3), 3 LGL leukemia patients with STAT5b mutation (Patients 4, 5, and 6), and 2 LGL leukemia patients without STAT3/STAT5b mutation (Patients 7 and 8) with CD8 and NK-cell samples from healthy controls to assess different gene expression patterns between samples.

2013-04-15 | E-MTAB-1611 | biostudies-arrayexpress

Exacerbated T cell lymphoma in NOD.Stat5bTg mice is caused by selective activation of Stat5b in CD8+ thymocytes and can be prevented by inhibition of the Stat5b signaling pathway with chemoprevention agents

Project description:This study demonstrated that genetic background is critical to the STAT5B-mediated lymphomagenesis probably through regulation of STAT5B activation, which results in the alteration of many tumorigenic genes. Chemopreventive compounds that can reduce STAT5B phosphorylation and/or the STAT5B signaling pathway can efficiently block lymphomagenesis, demonstrating that the NOD.Stat5bTg mouse is an excellent model for testing novel chemopreventive strategies. To elucidate the molecular mechanism underlying the activation of Stat5b upon lymphoma onset, we profiled gene expression in thymocytes of NOD.Stat5b mice, Gene expression was analyzed with the Illumina's MouseRef-8 v2.0 Expression beadchips

2012-04-09 | E-GEOD-31526 | biostudies-arrayexpress

A STAT5B-CD9 axis determines self-renewal in hematopoietic and leukemic stem cells

Project description:The transcription factors STAT5A and STAT5B are critical in hematopoiesis and leukemia. They are widely believed to have redundant functions but we describe a unique role for STAT5B in driving the self-renewal of hematopoietic and leukemic stem cells (HSCs/LSCs). We find STAT5B to be specifically activated in HSCs and LSCs, where it induces many genes associated with quiescence and self-renewal, including the surface marker CD9. Levels of CD9 represent a prognostic marker for patients with STAT5-driven leukemia and our findings suggest that anti-CD9 antibodies may be useful in their treatment to target and eliminate LSCs. We show that it is vital to consider STAT5A and STAT5B as distinct entities in normal and malignant hematopoiesis.

2021-12-31 | GSE178648 | GEO

Gene expression profiling of Type II Enteropathy-associated T-cell lymphoma

Project description:Type II Enteropathy-associated T-cell lymphoma (Type II EATL) is an aggressive intestinal T-cell lymphoma with poor prognosis and has not been molecularly profiled. Through targeted amplicon sequencing, we identified a large portion of Type II EATL samples that harbor mutations in the STAT5B, JAK3 and GNAI2 genes. Here we performed gene expression profiling on four Type II EATL samples in order to better characterize this disease. As Type II EATL is suggested to arise from CD8+ IELs, we integrated our data with publicly available profile of CD8Î±Î± and CD8Î±Î² T-cells from healthy donors (GSE33374). Gene expression profiling independently demonstrated strong enrichment of several aspects of GPCR and JAK-STAT signaling pathways. Moreover, an significant association was identified with genes containing STAT5B binding sites in their promoters. Microarray gene expression profiling was performed on 4 Type II Enteropathy-associated T-cell lymphoma and a combination of unsupervised and supervised clustering was performed to determine any differentially activated pathways between samples with tumor and healthy human CD161++CD8aa and CD161++CD8ab T cells (found under accession number GSE33374)

2016-03-03 | E-GEOD-70652 | biostudies-arrayexpress

Andersson_et_al_2013

Project description:LGL leukemia is chronic clonal lymphoproliferative disorder, characterized by expansion of cytotoxic CD8+ T-cells or NK-cells. We compared gene expression of 2 LGL leukemia patients with STAT3 mutation (Patients 11 and 12) and 2 LGL leukemia patients without STAT3/STAT5b mutation (Patients 9 and 10) with CD8 and CD4 samples from healthy controls to assess different gene expression patterns between samples.

2013-11-14 | E-MTAB-2068 | biostudies-arrayexpress

Essential role of STAT5 tyrosine phosphorylation in vivo

Project description:STAT5 proteins are vital for lymphocyte development and function. Tyrosine phosphorylation of a C-terminal tyrosine is the key event in cytokine activation of STAT5A and STAT5B. However, the role of STAT5 tyrosine phosphorylation has not been assessed in vivo. Here we generated Stat5a and Stat5b tyrosine mutant knock-in (KI) mice and found that these animals had greatly reduced CD8+ T cell numbers. These cells exhibited profoundly diminished proliferation in response to IL-2, correlating with greatly reduced IL-2-induced pRB and a block in the G1-->S phase transition. The mutant cells also exhibited decreased IL-2-mediated activation of pERK and pAKT, which can in part be attributed to diminished IL-2-induced expression of IL-2R-beta and IL-2R-gamma. Our findings highlight that the tyrosine phosphorylation of both STAT5A and STAT5B is essential for maximal IL-2 signaling and elucidate the molecular basis for achieving an optimal mitogenic effect of IL-2 on CD8+ T cells.

2023-11-06 | MSV000093320 | MassIVE

Phosphoproteomic analyses of IL-2 signaling reveals integrated JAK-dependent and independent phosphorylation networks that drive cytotoxic T cell fate

Project description:High-resolution mass spectrometry analysis of Interleukin 2 (IL-2) and Janus kinase (JAK) controlled protein phosphorylations in cytotoxic T lymphocytes (CTL) revealed JAKs coupled IL-2 receptors to diverse and complex serine/threonine kinase-substrate networks. These involved intricate, co-ordinated phosphorylation of transcription factors, chromatin regulators within the nuclear environment, cytosolic mRNA translational machinery, regulators of GTPases, vesicle trafficking proteins and the actin and microtubule cytoskeleton. We also identified an IL-2-JAK independent SRC family Tyr kinase controlled signaling network that regulates ~10% of the CTL phosphoproteome. One key signaling pathway in CTL is mediated by phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and the serine/threonine kinase AKT. Strikingly, SRC family kinase dependent but JAK independent signaling controlled PIP3 levels and AKT activity in CTL. IL-2-JAK controlled signaling pathways thus coordinate with IL-2 independent networks of protein phosphorylation to program CTL fate.

2016-08-25 | PXD004645 | Pride

A cell competition-based drug screen identifies a novel compound that induces dual c-Myc degradation and p53 activation

Project description:BCR-Abl is a driver oncogene that causes chronic myeloid leukemia and a subset of acute lymphoid leukemias. Although tyrosine kinase inhibitors provide an effective treatment for these diseases, they generally do not kill leukemic stem cells. Leukemic stem cells are cancer-initiating cells that compete with normal hematopoietic stem cells for the bone marrow niche. Using BCR-Abl as a model oncogene, we performed a drug screen based on competition between isogenic untransformed cells and BCR-Abl-transformed cells, and identified several compounds that selectively target BCR-Abl-transformed cells. Systems-level analysis of one of these novel compounds, DJ34, revealed that it induced depletion of c-Myc and activation of p53. c-Myc depletion occurred in a wide range of tumor types, including leukemia, lymphoma, lung, glioblastoma and breast cancer. Further analyses revealed that DJ34 interferes with c-Myc synthesis at the level of transcription, and we provide data showing that DJ34 is a DNA intercalator and topoisomerase II inhibitor. Physiologically, DJ34 induced apoptosis, cell cycle arrest and cell differentiation, and primary leukemic stem cells were particularly sensitive to DJ34. Taken together, we have identified a novel compound that dually targets c-Myc and p53 in a wide variety of cancers, and with particularly strong activity against leukemic stem cells.

2020-12-07 | PXD018812 | Pride

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