Casein kinase 1δ/ε inhibition suppresses CLL through cell-intrinsic and microenvironmental mechanisms
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE304722 | GEO | 2026/03/31
REPOSITORIES: GEO
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Project description:Chronic lymphocytic leukemia (CLL) is a consequence of pathological B cell accumulation in blood and lymphoid organs. Due to high refractoriness, CLL is considered incurable which calls for novel therapeutic options. Previously, we showed casein kinase 1δ/ε (CK1δ/ε) inhibition prolonged survival of Eµ-TCL1 mice with CLL-like disease. Herein, we elucidate mechanisms mediating CK1δ/ε inhibition efficacy in CLL suppression. Using in vivo Eµ-TCL1 adoptive transfer (AT) model, we showed CK1δ/ε inhibition mediated cell cycle slowdown and CLL cell accumulation at S/G2 interface. This observation was validated using multiple CLL cell lines and EdU/Click-iT reaction applied in vivo. Furthermore, we showed CK1δ/ε inhibition led to T cell decrease in lymph nodes (LN). Using system mimicking LN microenvironment in vitro, we observed CK1δ/ε inhibition triggered downregulation of nuclear factor κ B (NFκB) pathway that acts downstream of T-cell-mediated CD40L:CD40 stimulus, inducing CLL cell proliferation. Finally, we showed CK1δ/ε inhibition counteracted proliferation of CLL cells from wide range of patients, with lower efficacy only in patients bearing TP53 defects.
2026-03-31 | GSE305855 | GEO
Project description:RNA-sequencing was used to determine gene expression of 4 Eµ-TCL1 (control) and 4 Eµ-TCL1 Zap70-ki mice which developed CLL.
2021-07-07 | GSE159908 | GEO
Project description:Aberrant CXCR4 activity has been implicated in lymphoma pathogenesis, disease progression and resistance to therapies. Using a mouse model with a gain-of-function CXCR4 mutation (CXCR4C1013G) that hyperactivates CXCR4 signaling, we identified CXCR4 as a crucial activator of multiple key oncogenic pathways. CXCR4 hyperactivation furthermore resulted in an expansion of transitional B1 lymphocytes, which represent the precursors of chronic lymphocytic leukemia (CLL). Indeed, CXCR4 hyperactivation led to a significant acceleration of disease onset and a more aggressive phenotype in the murine Eµ-TCL1 CLL model. Hyperactivated CXCR4 signaling cooperated with TCL1 to cause a distinct oncogenic transcriptional program in B cells, characterized by PLK1/FOXM1-associated pathways. In accordance, Eµ-TCL1;CXCR4C1013G B cells enriched a transcriptional signature from patients with Richter’s syndrome, an aggressive transformation of CLL. In summary, we here identify CXCR4 hyperactivation as a co-driver of an aggressive lymphoma phenotype. Here we make available the transcriptomic data of CD19+ B cells from bone marrow and spleen of 6-week-old WT, CXCR4C1013G, Eµ-TCL1 and Eµ-TCL1;CXCR4C1013G mice.
2021-06-27 | GSE178959 | GEO
Project description:Chronic lymphocytic leukemia (CLL) is a malignant lymphoproliferative disorder characterized by the accumulation of small mature B cells in blood and secondary lymphoid tissues. Novel drugs, such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, have greatly improved survival expectations of CLL patients, nevertheless acquired drug resistance represents a major challenge the molecular mechanisms of which have not been elucidated yet. In order to fill this knowledge gap, we generated a mouse model of ibrutinib resistance by treating mice upon adoptive transfer of Eµ-TCL1 leukemia (TCL1-CLL) continuously with ibrutinib. After an initial response to the treatment, relapse under therapy occurs with an aggressive outgrowth of the malignant cells, resembling observations in patients. To unravel relapse mechanism, we performed transcriptome and proteome analyses of sorted TCL1-CLL cells both during treatment and after relapse. Comparative analysis of these omics layers suggested alterations in the proteasome activity as a driver of ibrutinib resistance. Accordingly, we showed that preclinical treatment with the irreversible proteasome inhibitor (PI) carfilzomib administered upon ibrutinib resistance prolonged survival of mice, thus acting as salvage therapy. Longitudinal proteomic analysis of CLL patients with ibrutinib resistance identified deregulation in protein post-translational modifications. In addition, CLL cells from ibrutinib-resistant patients effectively responded to several PIs in co-culture assays. Altogether, our results from orthogonal omics approaches identified proteasome inhibition as potentially attractive innovative salvage treatment option for CLL patients resistant or refractory to ibrutinib.
2024-12-10 | PXD037314 | Pride
Project description:Chronic lymphocytic leukemia (CLL) is a malignant lymphoproliferative disorder characterized by the accumulation of small mature B cells in blood and secondary lymphoid tissues. Novel drugs, such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, have greatly improved survival of CLL patients, nevertheless acquired drug resistance represents a major challenge the molecular mechanisms of which have not been fully elucidated yet. To overcome this limitation, we generated a mouse model of ibrutinib resistance by treating mice upon adoptive transfer of Eµ-TCL1 leukemia (TCL1-CLL) continuously with ibrutinib. After an initial response to the treatment, relapse under therapy occurs with an aggressive outgrowth of malignant cells, resembling observations in patients. To unravel relapse mechanism, we performed transcriptome and proteome analyses of sorted TCL1-CLL cells both during treatment and after relapse. Comparative analysis of these omics layers suggested alterations in the proteasome activity as a driver of ibrutinib resistance. Accordingly, we showed that preclinical treatment with the irreversible proteasome inhibitor (PI) carfilzomib administered upon ibrutinib resistance prolonged survival of mice, thus acting as salvage therapy. Longitudinal proteomic analysis of CLL patients with ibrutinib resistance identified deregulation in protein post-translational modifications. In addition, CLL cells from ibrutinib-resistant patients effectively responded to several PIs in co-culture assays. Altogether, our results from orthogonal omics approaches identified proteasome inhibition as potentially attractive salvage treatment option for CLL patients resistant or refractory to ibrutinib.
2024-12-10 | PXD053512 | Pride
Project description:B cell chronic lymphocytic leukemia (CLL) is often preceded by a benign monoclonal or oligoclonal CD5+ B cell lymphocytosis. We have generated transgenic mice expressing a catalytically inactive, dominant-negative recombination activating gene 1 (dnRAG1 mice) in the periphery. These animals develop an early-onset indolent CD5+ B cell lymphocytosis, caused in part by a defect in secondary V(D)J rearrangements initiated to alter autoreactive B cell receptor specificity. Hypothesizing that the CD5+ B cells accumulating in dnRAG1 mice represent a CLL precursor, we crossed dnRAG1 mice with CLL-prone Eµ-TCL1 mice to determine whether dnRAG1 expression in Eµ-TCL1 mice accelerates the onset of CLL-like disease. We find that CD5+ B cell expansion and CLL progression occurs more rapidly and uniformly in double-transgenic mice (DTG mice) compared to Eµ-TCL1 mice, but with similar phenotypic and leukemogenic features. To gain insight into genes or pathways responsible for CD5+ B cell accumulation in the transgenic mice, we performed comparative gene expression profiling studies using normal and CD5+ B cells isolated from wild-type and transgenic mice at either 12 weeks of age (pre-leukemia) or at CLL onset in DTG mice (using age-matched wild-type and single-transgenic mice as controls). These analyses confirm the upregulation of tolerogenic genes in CD5+ B cells and reveal a possible role for prolactin signaling in the regulation of receptor editing. This study suggests that a failure to remodel B cell antigen receptor genes in response to autoreactivity may promote the benign accumulation of CD5+ B cells, which may then be subjected to secondary genetic lesions that promote CLL progression. dnRAG1 mice were bred to Eµ-TCL1 mice to obtain cohorts of wild-type (WT), single-transgenic (dnRAG1 and Eµ-TCL1), and DTG mice. Splenic CD19+B220hiCD5- B cells from WT mice or CD19+CD5+ B cells from transgenic mice were purified using fluorescence activated cell sorting (FACS). Biotin end-labeled cDNA prepared from the sorted cells was hybridized to Mouse Gene 1.0 ST Arrays. These experiments were performed two independent times: once with a cohort of 12-week-old mice, and once with older mice (>34 weeks old) consisting of two ill DTG mice and their age-matched counterparts. At least two biological replicates were used where possible.
2013-06-04 | E-GEOD-44940 | biostudies-arrayexpress
Project description:Purpose: Karyotype screening in patients with chronic lymphocytic leukemia (CLL) has identified a rare chromosome translocation, t(X;14)(q28;q32), placing the mature T cell proliferation 1 (MTCP1) gene under transcriptional control of the immunoglobulin (IGH) locus. To establish the role of MTCP1 as a driving gene in CLL, we generated a novel mouse model (Eµ-MTCP1) which recapitulates overexpression of MTCP1 in murine immature and mature B cells. Eµ-MTCP1 mice developed a CLL-like disease found in the blood, spleen, lymph nodes, and other tissues. As the MTCP1 protein shares significant homology with the TCL1A oncoprotein, and the Eµ-TCL1 mouse model is widely used as an preclinical tool in CLL due to the development of a CLL-like disease in the blood, spleen, and other tissues, we aimed to evaluate the transcriptome between the CLL-like disease of Eµ-MTCP1 and Eµ-TCL1 mice. Methods: Transgenic Eµ-MTCP1 mice were generated on a C57BL/6NTac background at The Ohio State University Comprehensive Cancer Center’s Transgenic Mouse Facility via pronuclear injection of linear constructs derived from a plasmid vector encoding murine VH promoter-IgH-Eμ enhancer elements followed by human cDNA encoding the p13 kDa MTCP1 protein. Eµ-MTCP1 and Eµ-TCL1 mice were aged and monitored for development of CLL-like disease my monthly flow cytometry assessment of the blood. Upon reaching significant accumulation in the blood (>60%), mice were randomly chosen for euthanization and cell populations were isolated from the spleen according to previously described protocols. From this suspension, B cells were isolated using EasySepTM mouse pan B cell isolation kit (STEMCELL Technologies; Cat #19844). Cell pellets were captured and washed in PBS on ice prior to resuspension in TRIzol reagent and stored at -80°. Total RNA was isolated from TRIzol suspensions using a chloroform/ethanol extraction method and quantified via Qubit RNA HS Assay kit (Invitrogen). The Clontech SMARTer v4 kit (Takara Bio USA, Inc.) was used for global preamplification. Illumina sequencing libraries were derived from the resultant cDNA using the Illumina Nextera XT DNA Library Prep Kit following manufacturer’s instructions. RNA-sequencing libraries were prepared with the Illumina Tru-Seq stranded kit and sequenced on a Hiseq 4000 targeting 40x10E6 fragments per sample. Transcript-level abundances were estimated using Salmon with the genocode mouse release 23, imported using tximport, with normalization and differential expression computed with DESeq2. Data processing was performed according to the CLEAR workflow, which identifies reliably quantifiable transcripts in low-input RNA-seq for differentially expressed gene (DEG) transcripts using gene coverage profiles. MiXCR (v3.0.5) was used with default parameters except the rnaseq alignment was replaced with kaligner2 to identify preprocessed reads containing CDR3 regions from B-cell heavy, kappa, and lambda chains, generating a list of unique CDR3 sequences associated with their relative abundances and specific V(D)J gene usage. MiXCR then generates a list of unique CDR3 sequences associated with their relative abundances and specific V(D)J gene usage. To verify expression of the human MTCP1 and TCL1 transgene (hMTCP1 & hTCL1) in mice, transcript level abundances were estimated using Salmon with a modified gencode mouse reference that contained sequences from human MTCP1 and human TCL1 genes extracted from the grch38 human reference. Results & Conclusion: Across splenic B cells isolated from both Eµ-MTCP1 and Eµ-TCL1 mice there was prominent usage of distinct heavy chain BCR gene loci in each mouse analyzed. In contrast, wildtype mice exhibited high degree of variability in heavy chain V gene usage without dominant emergence of any gene, indicative of a heterogeneous mixture of splenic B cells. Similar patterns suggesting clonal leukemic populations were observed by kappa and lamba light chain usage. The complexity and aggressive nature of human CLL is often stratified by IGHV mutation status of the malignant B cell population. The most abundant tumorigenic clones isolated from spleens of Eµ-MTCP1 and Eµ-TCL1 mice both exhibited low mutational burden in IGHV, well below the threshold for classification as “mutated." The low mutational burden in this region is consistent with the aggressive, IGHV-unmutated, subtype of human CLL. Moreover, we aimed to determine the overall transcriptional profile of these monoclonal tumor cells and to establish relation to that of the CLL-like cells in Eµ-TCL1 mice. Principal component analysis of the global transcription profile revealed distinct clustering of Eµ-MTCP1 and Eµ-TCL1 tumor cell transcriptomes along PC2, with significant segregation from wildtype littermates across PC1. Analysis of the overall gene expression pattern between Eµ-MTCP1 and Eµ-TCL1 transgenic strains revealed a significant overlap in genes most variable from B cells of wildtype animals. A considerable degree of overlap in gene expression was noted when directly comparing Eµ-MTCP1 and Eµ-TCL1 expression profiles, with a total of only 92 of 27,054 analyzed genes having significant variation (p<0.001) from one transgenic model to the other.
2021-08-24 | GSE176094 | GEO
Project description:Analysis of the effect of CLL development on differentation and gene expression of splenic monocytes. C57BL/6 mice were transplanted with murine CLL cells from Eµ-TCL1 mice and after 6 weeks total RNA was isolated from splenic monocytes from leukemic mice and matched WT controls.
2015-07-01 | E-GEOD-66858 | biostudies-arrayexpress
Project description:B cell chronic lymphocytic leukemia (CLL) is often preceded by a benign monoclonal or oligoclonal CD5+ B cell lymphocytosis. We have generated transgenic mice expressing a catalytically inactive, dominant-negative recombination activating gene 1 (dnRAG1 mice) in the periphery. These animals develop an early-onset indolent CD5+ B cell lymphocytosis, caused in part by a defect in secondary V(D)J rearrangements initiated to alter autoreactive B cell receptor specificity. Hypothesizing that the CD5+ B cells accumulating in dnRAG1 mice represent a CLL precursor, we crossed dnRAG1 mice with CLL-prone Eµ-TCL1 mice to determine whether dnRAG1 expression in Eµ-TCL1 mice accelerates the onset of CLL-like disease. We find that CD5+ B cell expansion and CLL progression occurs more rapidly and uniformly in double-transgenic mice (DTG mice) compared to Eµ-TCL1 mice, but with similar phenotypic and leukemogenic features. To gain insight into genes or pathways responsible for CD5+ B cell accumulation in the transgenic mice, we performed comparative gene expression profiling studies using normal and CD5+ B cells isolated from wild-type and transgenic mice at either 12 weeks of age (pre-leukemia) or at CLL onset in DTG mice (using age-matched wild-type and single-transgenic mice as controls). These analyses confirm the upregulation of tolerogenic genes in CD5+ B cells and reveal a possible role for prolactin signaling in the regulation of receptor editing. This study suggests that a failure to remodel B cell antigen receptor genes in response to autoreactivity may promote the benign accumulation of CD5+ B cells, which may then be subjected to secondary genetic lesions that promote CLL progression.
2013-06-04 | GSE44940 | GEO
Project description:Chronic lymphocytic leukemia (CLL) is a malignant lymphoproliferative disorder characterized by the accumulation of small mature B cells in blood and secondary lymphoid tissues. Novel drugs, such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, have greatly improved survival expectations of CLL patients, nevertheless acquired drug resistance represents a major challenge and the complete molecular mechanisms of which have not been elucidated yet. In order to fill this knowledge gap, we generated a mouse model of ibrutinib resistance by treating mice upon adoptive transfer of Eµ-TCL1 leukemia (TCL1-CLL) continuously with ibrutinib. After an initial response to the treatment, relapse under therapy occurs with an aggressive outgrowth of the malignant cells, resembling observations in patients. To unravel relapse mechanism, we performed transcriptome and proteome analyses of sorted TCL1-CLL cells both during treatment and after relapse. Comparative analysis of these omics layers suggested alterations in the proteasome activity as a driver of ibrutinib resistance. Accordingly, we showed that preclinical treatment with the irreversible proteasome inhibitor (PI) carfilzomib administered upon ibrutinib resistance prolonged survival of mice, thus acting as salvage therapy. Longitudinal proteomic analysis of CLL patients with ibrutinib resistance identified deregulation in protein post-translational modifications. In addition, CLL cells from ibrutinib-resistant patients effectively responded to several PIs in co-culture assays. Altogether, our results from orthogonal omics approaches identified proteasome inhibition as potentially attractive innovative salvage treatment option for CLL patients resistant or refractory to ibrutinib.
2024-10-29 | GSE215414 | GEO