The PAX5-JAK2 translocation acts as a dual-hit mutation that promotes aggressive B-cell leukemia via nuclear STAT5 activation
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ABSTRACT:
PROVIDER: PRJNA731504 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14607400_1.fastq.gz | Fastqsanger.gz | |||
| SRR14607400_2.fastq.gz | Fastqsanger.gz | |||
| SRR14607401.fastq.gz | Fastqsanger.gz | |||
| SRR14607402.fastq.gz | Fastqsanger.gz | |||
| SRR14607403.fastq.gz | Fastqsanger.gz |
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Project description:While PAX5 is an important tumor suppressor in B-ALL, it is also involved in oncogenic translocations coding for PAX5 fusion proteins. PAX5-JAK2 encodes a protein consisting of the PAX5 DNA-binding region fused to the constitutively active JAK2 kinase domain. Here, we studied the oncogenic function of PAX5-JAK2 in a mouse model expressing it from the endogenous Pax5 locus. The Pax5Jak2/+ mice rapidly developed an aggressive B-ALL in the absence of another cooperating mutation. The DNA-binding function and kinase activity of Pax5-Jak2, as well as IL-7 signaling, all contributed to leukemia development. Interestingly, all Pax5Jak2/+ tumors lost the wild-type Pax5 allele, allowing efficient DNA binding of Pax5-Jak2. While we could not find evidence for a nuclear role of Pax5-Jak2 as an epigenetic regulator, active phosphorylated Stat5 was present at a high level in Pax5Jak2/+ B-ALL tumors, consistent with increased expression of Stat5 target genes. Together, these data identified Pax5-Jak2 as an important nuclear driver of leukemia formation by maintaining phosphorylated Stat5 levels in the nucleus.
2022-02-04 | GSE174775 | GEO
Project description:While PAX5 is an important tumor suppressor gene in B-cell acute lymphoblastic leukemia (B-ALL), it is also involved in oncogenic translocations coding for diverse PAX5 fusion proteins. PAX5-JAK2 encodes a protein consisting of the PAX5 DNA-binding region fused to the constitutively active JAK2 kinase domain. Here, we studied the oncogenic function of the PAX5-JAK2 fusion protein in a mouse model expressing it from the endogenous Pax5 locus, resulting in inactivation of one of the two Pax5 alleles. Pax5Jak2/+ mice rapidly developed an aggressive B-ALL in the absence of another cooperating exogenous gene mutation. The DNA-binding function and kinase activity of Pax5-Jak2 as well as IL-7 signaling contributed to leukemia development. Interestingly, all Pax5Jak2/+ tumors lost the remaining wild-type Pax5 allele, allowing efficient DNA-binding of Pax5-Jak2. While we could not find evidence for a nuclear role of Pax5-Jak2 as an epigenetic regulator, high levels of active phosphorylated STAT5 and increased expression of STAT5 target genes were seen in Pax5Jak2/+ B-ALL tumors, implying that nuclear Pax5-Jak2 phosphorylates STAT5. Together, these data reveal Pax5-Jak2 as an important nuclear driver of leukemogenesis by maintaining phosphorylated STAT5 levels in the nucleus.
| S-EPMC8982625 | biostudies-literature
Project description:While PAX5 is an important tumor suppressor gene in B-cell acute lymphoblastic leukemia (B-ALL), it is also involved in oncogenic translocations coding for diverse PAX5 fusion proteins. PAX5-JAK2 encodes a protein consisting of the PAX5 DNA-binding region fused to the constitutively active JAK2 kinase domain. Here, we studied the oncogenic function of the PAX5-JAK2 fusion protein in a mouse model expressing it from the endogenous Pax5 locus, resulting in inactivation of one of the two Pax5 alleles. Pax5Jak2/+ mice rapidly developed an aggressive B-ALL in the absence of another cooperating exogeneous gene mutation. The DNA-binding function and kinase activity of Pax5-Jak2 as well as IL-7 signaling contributed to leukemia development. Interestingly, all Pax5Jak2/+ tumors lost the remaining wild-type Pax5 allele, allowing efficient DNA binding of Pax5-Jak2. While we could not find evidence for a nuclear role of Pax5-Jak2 as an epigenetic regulator, high levels of active phosphorylated STAT5 and increased expression of STAT5 target genes were seen in Pax5Jak2/+ B-ALL tumors, implying that nuclear Pax5-Jak2 phosphorylates STAT5. Together, these data reveal Pax5-Jak2 as an important nuclear driver of leukemogenesis by maintaining phosphorylated STAT5 levels in the nucleus.
| S-SCDT-EMBOJ-2021-108397 | biostudies-other
Project description:PAX5-JAK2 has recently been identified as a novel recurrent fusion gene in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) but the function of the encoded chimeric protein has not yet been characterized in detail. Herein we show that the PAX5-JAK2 chimera, which consists of the DNA-binding paired domain of PAX5 and the active kinase domain of JAK2, is a nuclear protein that has the ability to bind to wild-type PAX5 target loci. Moreover, our data provide compelling evidence that PAX5-JAK2 functions as nuclear catalytically active kinase that autophosphorylates and in turn phosphorylates and activates downstream STATs in an apparently non-canonical mode. The chimeric protein also enables cytokine-independent growth of Ba/F3 cells and, therefore, possessing transforming potential. Importantly, the kinase activity of PAX5-JAK2 can be efficiently blocked by JAK2 inhibitors rendering it a potential target for therapeutic intervention. Together, our data show that PAX5-JAK2 simultaneously deregulates the PAX5 downstream transcriptional program and activates the JAK-STAT signaling cascade, and thus, by interfering with these two important pathways, may promote leukemogenesis.
2014-12-29 | GSE56449 | GEO
Project description:STAT5 is critical for differentiation, proliferation and survival of progenitor B cells suggesting a possible role in Acute Lymphoblastic Leukemia (ALL). Herein, we show increased expression of activated STAT5 in ALL patients, which correlates with treatment outcome. Mutations in Ebf1 and Pax5, genes critical for B cell development have also been identified in human ALL. To determine whether mutations in Ebf1 or Pax5 synergize with STAT5 activation to induce ALL we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice heterozygous for Ebf1 or Pax5. Haploinsufficiency of either Pax5 or Ebf1 synergized with Stat5b-CA to rapidly induce ALL in 100% of the mice. The leukemic cells displayed reduced expression of both Pax5 and Ebf1 but this had little affect on most EBF1 or PAX5 target genes. However, a subset of these genes was deregulated and included a large percentage of potential tumor suppressor genes and oncogenes. Further, most of these genes appear to be jointly regulated by both EBF1 and PAX5. Our findings suggest a model whereby small perturbations in a self-reinforcing network of transcription factors critical for B cell development, specifically PAX5 and EBF1, cooperate with STAT5 activation to initiate ALL. Gene expression profiling was performed on cells isolated from lymph nodes of Stat5b-CA x Ebf1+/- and Stat5b-CA x Rag2-/- leukemic mice and pre B cells sorted from bone marrow of C57BL/6 mice and Stat5b-CA transgenic mice. 17 Samples.
2011-05-09 | E-GEOD-25645 | biostudies-arrayexpress
Project description:STAT5 is critical for differentiation, proliferation and survival of progenitor B cells suggesting a possible role in Acute Lymphoblastic Leukemia (ALL). Herein, we show increased expression of activated STAT5 in ALL patients, which correlates with treatment outcome. Mutations in Ebf1 and Pax5, genes critical for B cell development have also been identified in human ALL. To determine whether mutations in Ebf1 or Pax5 synergize with STAT5 activation to induce ALL we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice heterozygous for Ebf1 or Pax5. Haploinsufficiency of either Pax5 or Ebf1 synergized with Stat5b-CA to rapidly induce ALL in 100% of the mice. The leukemic cells displayed reduced expression of both Pax5 and Ebf1 but this had little affect on most EBF1 or PAX5 target genes. However, a subset of these genes was deregulated and included a large percentage of potential tumor suppressor genes and oncogenes. Further, most of these genes appear to be jointly regulated by both EBF1 and PAX5. Our findings suggest a model whereby small perturbations in a self-reinforcing network of transcription factors critical for B cell development, specifically PAX5 and EBF1, cooperate with STAT5 activation to initiate ALL.
2011-05-09 | GSE25645 | GEO
Project description:Cellular signal transduction is governed by multiple feedback mechanisms to elicit robust cellular decisions. We combined mathematical modeling and extensive time-resolved data sets in primary erythroid progenitor cells and dissected the roles of the two transcriptional feedback regulators of the SOCS family, CIS and SOCS3 in JAK2/STAT5 signaling. Our model revealed that both feedbacks are most effective at different ligand concentration ranges. To identify the relevant transcriptional feedback regulators that are involved in attenuation of Epo-induced JAK2-STAT5 signaling in addition to CIS, we performed a time-resolved genome-wide expression profiling of murine erythroid progenitor cells at the colony forming unit erythroid (CFU-E) stage up to 24 and 7 hours after EPO stimulation and in control, repectively. The analysis identified SOCS3 as the only further de novo regulated gene upon Epo-induced JAK2-STAT5 signaling. From subsequent mathematical modeling, we calculated the STAT5 response in previously unobserved Epo concentrations, which provided a quantitative link between cell survival and the integrated response of STAT5 in the nucleus. In conclusion, our combined modeling approach revealed novel insights into the orchestrated action of feedback control to regulate STAT5-mediated survival decisions over a broad range of ligand concentrations. Freshly sorted CFU-E cells were starved for 1 h in Panserin 401 supplemented with BSA and 50 µM β-Mercaptoethanol. Subsequently, cells were stimulated with 0.5 U/ml Epo or left untreated and RNA was extracted at different time points (0,1,2,3,4,5,6,7,8,14,19,24 hrs after Epo stimulation and at 0,1,2,3,4,5,6,7 hrs without Epo treatment) using the RNeasy Mini Plus Kit (Qiagen, Hilden, Germany).
2011-06-30 | E-GEOD-26151 | biostudies-arrayexpress
Project description:Cellular signal transduction is governed by multiple feedback mechanisms to elicit robust cellular decisions. We combined mathematical modeling and extensive time-resolved data sets in primary erythroid progenitor cells and dissected the roles of the two transcriptional feedback regulators of the SOCS family, CIS and SOCS3 in JAK2/STAT5 signaling. Our model revealed that both feedbacks are most effective at different ligand concentration ranges. To identify the relevant transcriptional feedback regulators that are involved in attenuation of Epo-induced JAK2-STAT5 signaling in addition to CIS, we performed a time-resolved genome-wide expression profiling of murine erythroid progenitor cells at the colony forming unit erythroid (CFU-E) stage up to 24 and 7 hours after EPO stimulation and in control, repectively. The analysis identified SOCS3 as the only further de novo regulated gene upon Epo-induced JAK2-STAT5 signaling. From subsequent mathematical modeling, we calculated the STAT5 response in previously unobserved Epo concentrations, which provided a quantitative link between cell survival and the integrated response of STAT5 in the nucleus. In conclusion, our combined modeling approach revealed novel insights into the orchestrated action of feedback control to regulate STAT5-mediated survival decisions over a broad range of ligand concentrations.
2011-06-30 | GSE26151 | GEO
Project description:PAX5-KIDINS220 (PAX5-K220) is a novel chimeric fusion gene identified in a pediatric Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) patient, but the function of the encoded fusion protein has not yet been analyzed.We successfully generated PAX5-K220 expressing cells and demonstrate that PAX5-K220 is a nuclear protein. In addition, PAX5-K220 activates JAK2-STAT5 pathway through the repression of Socs5, a known negative regulator of JAK-STAT pathway. However, although identified in Ph-like ALL, PAX5-K220 does not induce IL-3-independent proliferation when transduced in the IL-3-dependent Ba/F3 murine leukemia cells, but rather attenuates growth. Luciferase reporter assay reveals that PAX5-K220 inhibits wild type PAX5 transcriptional activity in a dominant-negative fashion like other PAX5-related fusion proteins, and may contribute to lymphocyte differentiation block. These results reveal that PAX5-K220 certainly shares the character with other PAX5-related fusion proteins rather than other fusion proteins with tyrosine kinase activity identified in Ph-like ALL, and did not contribute to proliferation activity.
2019-03-01 | GSE127485 | GEO
Project description:Increasing evidence has revealed a close relationship between circular RNAs (circRNAs) and the regulatory process of cell aging. Exploring the role and mechanism of circRNAs in cellular senescence may help to identify new anti-aging therapeutic targets. In the present study, we investigated the role and regulatory mechanism of hsa_circ_012707 in renal aging.High-throughput sequencing was performed to detect the differential expression of circRNAs in kidney tissues of the old and young groups. qRT-PCR confirmed that the expression of hsa_circ_0127071 in kidney tissue of the old group was significantly higher than that of the young group. SA-β-Gal, Masson Assay is used to evaluate the role of hsa_circ_0127071 in the aging process of kidney tissue.Using RIP, RNA pull down, and WB to study the interaction between hsa_circ_0127071 and aging related pathway proteins.In this study, we found that the expression of hsa_circ_0127071 in kidney tissue of the old group was significantly higher than that of the young group. The activity of JAK2/STAT5 signaling pathway was decreased after silencing EIF4A3, which could delay the aging process. On the basis of silencing EIF4A3 expression, the JAK2/STAT5 signaling pathway was activated by EPO processing, and the senescence of HGMCs increased. After treatment with LOS, the activity of JAK2/STAT5 pathway was decreased and the aging process of HGMCs was delayed. Our findings showed that hsa_circ_0127071 promoted renal aging, and confirmed the regulatory role of EIF4A3/hsa_circ_0127071/JAK2/STAT5 in the regulation of renal aging, providing a new therapeutic target for drug design and early diagnosis.
2024-12-05 | GSE245017 | GEO