Leukemic cells expressing NCOR1-LYN are sensitive to dasatinib in vivo in a patient-derived xenograft mouse model
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PROVIDER: PRJNA613667 | ENA |
REPOSITORIES: ENA
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Project description:Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a distinct subtype of B-ALL with a poor prognosis. Rearrangement of LYN is a recurrent genetic abnormality in Ph-like ALL, but functional analysis of LYN-related fusion genes identified in ALL has not been reported. In this study, we performed functional analysis of the NCOR1-LYN fusion gene identified in a pediatric Ph-like ALL patient to establish its potential for molecular targeted therapy. Retroviral transduction of interleukin (IL)-3-dependent Ba/F3 cells with NCOR1-LYN enabled IL-3-independent proliferation, with constitutive phosphorylation of the tyrosine residues of the LYN kinase domain in the fusion protein. Replacing tyrosine residues with phenylalanine in the LYN kinase domain abolished IL-3 independence. Tyrosine kinase inhibitor dasatinib killed Ba/F3 cells expressing NCOR1-LYN in vitro accompanied by dephosphorylation of the tyrosine residues of the LYN kinase domain in the fusion protein. In a patient-derived xenograft (PDX) mouse model, generated using leukemic cells from the NCOR1-LYN positive Ph-like ALL patient, dasatinib controlled the growth of leukemic cells in vivo and significantly extended the survival time of the PDX mice (p=0.03). Our data demonstrate that, like other kinase fusions identified in Ph-like ALL, the NCOR1-LYN rearrangement has proliferative activity, and that tyrosine phosphorylation of the LYN kinase domain is critical for IL-3 independent growth. Furthermore, in a preclinical model we demonstrate the efficacy in vivo of dasatinib as therapy for Ph-like ALL with a LYN rearrangement.
2020-03-21 | GSE147281 | GEO
Project description:LYN kinase is a tyrosine kinase, that regulates cellular homeostasis in a context-specific manner. Our group could show, that its expression in the leukemic microenvironment of chronic lymphocytic leukemia contributes to disease progression (Nguyen PH et al.; Cancer Cell; 2016). We analyzed the effect of LYN deficiency on murine splenic stromal cells by FACS-sorting stroma cells from Lyn(wt/wt) and Lyn(-/-) spleen (7AAD-Cd45-Cd71-Cd31-Cd26+Cd54+).
2023-02-10 | E-MTAB-12630 | biostudies-arrayexpress
Project description:LYN kinase is a tyrosine kinase, that regulates cellular homeostasis in a context-specific manner. Our group could show, that its expression in the leukemic microenvironment of chronic lymphocytic leukemia contributes to disease progression (Nguyen PH et al.; Cancer Cell; 2016). To analyze the effect of LYN kinase on the leukemia supportive phenotype of the bone marrow stromal cell line HS-5, we generated single cell clones of LYN deficient stroma cells. These cells were analyzed in a Multi-Omic approach, including microarray based analysis of the transcriptome.
2023-01-01 | E-MTAB-10980 | biostudies-arrayexpress
Project description:LYN kinase is a tyrosine kinase, that regulates cellular homeostasis in a context-specific manner. Our group could show, that its expression in the leukemic microenvironment of chronic lymphocytic leukemia contributes to disease progression (Nguyen PH et al.; Cancer Cell; 2016). To analyze the effect of LYN kinase on the leukemia supportive phenotype of the bone marrow stromal cell line HS-5, we generated single cell clones of LYN deficient stroma cells. These cells were analyzed in a Multi-Omic approach, including ATAC-Seq analysis of adapted epigenetic regulations.
2024-01-01 | E-MTAB-12531 | biostudies-arrayexpress
Project description:LYN kinase is a tyrosine kinase, that regulates cellular homeostasis in a context specific manner. Our group could show, that its expression in the leukemic microenvironment of chronic lymphocytic leukemia contributes to disease progression (Nguyen PH et al.; Cancer Cell; 2016). To analyze the effect of LYN kinase on the leukemia supportive phenotype of the bone marrow stromal cell line HS-5, we generated single cell clones of LYN deficient cells. These cells were analyzed in a Multi-Omic approach, including quantitative, label-free proteomic analysis of the Secretome.
2023-05-10 | PXD028855 | Pride
Project description:Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is associated with high rates of treatment failure and poor outcome. Activation of ABL/Src family kinases is found in ~10% of Ph-like ALL, which can be therapeutically targeted by tyrosine kinase inhibitors. LYN is a member of the ABL/Src-tyrosine kinase family. Somatic LYN rearrangements are found in 5 cases of hematopoietic malignancies so far, although none of them were treated with tyrosine kinase inhibitors. Case presentation: A 6-year-old boy with relapsed B-ALL had no response to reinduction chemotherapy. He was then treated with the ABL1 tyrosine kinase inhibitor dasatinib and achieved complete remission within 2 weeks. Haploidentical allogenic stem cell transplantation (allo-HSCT) was subsequently performed and maintenance therapy with dasatinib initiated 8 weeks post-transplantation. He has been in minimal residual disease negative remission for 10 months after allo-HSCT. Result: His bone marrow karyotype showed a balanced translocation between chromosomes 8 and 17, leading to a NCOR1-LYN fusion gene confirmed with sequencing. Conclusion: Although LYN overexpression is described in many AML and B-ALL patients, intragenic LYN rearrangement is a rare event. For the first time, we present evidence that dasatinib is effective in treating a pediatric B-ALL with NCOR-LYN fusion.
| S-EPMC7098965 | biostudies-literature
Project description:LYN kinase is a tyrosine kinase, that regulates cellular homeostasis in a context-specific manner. Our group could show, that its expression in the leukemic microenvironment of chronic lymphocytic leukemia contributes to disease progression (Nguyen PH et al.; Cancer Cell; 2016). To analyze the effect of LYN kinase on the leukemia supportive phenotype of the bone marrow stromal cell line HS-5, we generated single cell clones of LYN deficient stroma cells. These cells were analyzed in a Multi-Omic approach, including ARNA-Seq of stromal cells after 72h of coculture with primary human chronic lymphocytic leukaemia (CLL) samples.
2023-02-10 | E-MTAB-12629 | biostudies-arrayexpress
Project description:LYN kinase is a tyrosine kinase, that regulates cellular homeostasis in a context specific manner. Our group could show, that its expression in the leukemic microenvironment of chronic lymphocytic leukemia contributes to disease progression (Nguyen PH et al.; Cancer Cell; 2016). To analyze the effect of LYN kinase on the leukemia supportive phenotype of the bone marrow stromal cell line HS-5, we generated single cell clones of LYN deficient cells. These cells were analyzed in a Multi-Omic approach, including quantitative, label-free proteomic analysis of the Proteome / SILAC labelled analysis of the tyrosine phosphoproteome.
2023-05-10 | PXD030582 | Pride
Project description:To characterize the relationship between IRF5 and Lyn in innate immune responses at a genome-wide scale, we performed gene expression microarray analysis for wild-type (WT), Irf5-KO, Lyn-KO and Lyn/Irf5-DKO bone marrow-derived dendritic cells (BMDCs) with or without 6 h-stimulation with 150 nM CpG-B ODN. We extracted the transcripts that were upregulated by CpG-B ODN in WT BMDCs, further upregulated in Lyn-KO BMDCs and then downregulated in Lyn/Irf5-DKO BMDCs (fold change ≥ 2, false discovery rate < 0.05). When these 79 transcripts were sorted by their expression levels in Lyn-KO BMDCs, most of the top 20 genes (13 out of 20) were those encoding type I interferons (IFNs), indicating that Lyn particularly suppresses IRF5 induction of type I IFNs.
2016-07-25 | GSE63014 | GEO
Project description:The nuclear corepressors NCOR1 and NCOR2 interact with transcription factors involved in B cell development and potentially link these factors to alterations in chromatin structure and gene expression. Herein we demonstrate that NCOR1/2 deletion limits B cell differentiation via impaired recombination, attenuates pre-BCR-signaling, and enhances STAT5-dependent transcription. Furthermore, NCOR1/2-deficient B cells exhibited derepression of EZH2-repressed gene modules, including the p53 pathway. These alterations resulted in aberrant Rag1 and Rag2 expression and accessibility in proliferating cells. Whole-genome sequencing of Ncor1/2 DKO B cells identified increased number of structural variants compared to wildtype B cells with cryptic recombination signal sequences. Finally, deletion of Ncor1 alleles in mice facilitated leukemic transformation, while human leukemias with less NCOR1 correlated with worse survival. NCOR1 mutations in human leukemia correlated with increased RAG expression and increased number of structural variants. These studies illuminate how the corepressors NCOR1/2 regulate B cell differentiation and provide insights into how NCOR1/2 mutations may promote B cell transformation.
2022-08-30 | GSE208656 | GEO