The proto-oncogene TCL1A deregulates mitotic checkpoint transition and genomic stability in CLL
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PROVIDER: PRJNA791361 | ENA |
REPOSITORIES: ENA
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Project description:Upregulation of the proto-oncogene TCL1A is causally implicated in various B- and T-cell malignancies. High-level TCL1A correlates with aggressive disease features and inferior clinical outcomes. However, molecular and cell-biological consequences of TCL1A dysregulation are not fully elucidated. Here, we identify CDC20 and other molecules of the safeguarding cell cycle checkpoints as novel TCL1A-interactors. In different model systems of B-cell leukemia/lymphoma, TCL1A overexpression accelerated cell cycle transition, impaired apoptotic damage responses in association with pronounced chromosome mis-segregation and caused cellular aneuploidy. In primary CLL samples, low CDC20 expression correlated with high expression of TCL1A and more aggressive disease characteristics. In line, a low CDC20 expression was a marker for reduced progression-free survival in CLL patients. Finally, knockdown of CDC20 in TCL1A-initiated murine lymphomas promoted chromosome disbalances and leukemia outgrowth. Overall, we discovered a cell-cycle associated effect of TCL1A by interfering with a proficient cell cycle transition. This adds to our concept of TCL1A’s transforming impact by targeting genome stability.
2022-11-14 | PXD030773 | Pride
Project description:Upregulation of the proto-oncogene TCL1A is causally implicated in various B- and T-cell malignancies. High-level TCL1A correlates with aggressive disease features and inferior clinical outcomes. However, molecular and cell-biological consequences of TCL1A dysregulation are not fully elucidated. Here, we identify CDC20 and other molecules of the safeguarding cell cycle checkpoints as novel TCL1A-interactors. In different model systems of B-cell leukemia/lymphoma, TCL1A overexpression accelerated cell cycle transition, impaired apoptotic damage responses in association with pronounced chromosome mis-segregation and caused cellular aneuploidy. In primary CLL samples, low CDC20 expression correlated with high expression of TCL1A and more aggressive disease characteristics. In line, a low CDC20 expression was a marker for reduced progression-free survival in CLL patients. Finally, knockdown of CDC20 in TCL1A-initiated murine lymphomas promoted chromosome disbalances and leukemia outgrowth. Overall, we discovered a cell-cycle associated effect of TCL1A by interfering with a proficient cell cycle transition. This adds to our concept of TCL1A’s transforming impact by targeting genome stability.
2022-11-14 | PXD030776 | Pride
Project description:Upregulation of the proto-oncogene TCL1A is causally implicated in various B- and T-cell malignancies. High-level TCL1A correlates with aggressive disease features and inferior clinical outcomes. However, molecular and cell-biological consequences of TCL1A dysregulation are not fully elucidated. To analyze if TCL1A’s oncogenic activity depends on its subcellular localization, we transduced murine hematopoietic stem cells and progenitor cells (HSC/HPC) with three different human TCL1A variants, being wild type, membrane-localized myristoylated (myr) TCL1A, and TCL1A fused to a nuclear localization signal (nls). All three groups developed mostly B-cell leukemias/lymphomas and less frequently CD4/CD8 double-positive or double-negative T-cell leukemia/lymphomas. Mice transplanted with cells expressing nls-hTCL1A had a significantly shorter survival in comparison to mice harboring wt TCL1A. Gene set enrichment analysis of gene expression profiling data from B-cell tumors identified nuclear pathways including DNA repair, cell cycle, and mitotic spindle to be enriched in the nls-hTCL1A over the hTCL1A cohort.
2022-11-14 | GSE192409 | GEO
Project description:A Drosophila proto-oncogene homolog controls aggression via aminergic neurons
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Project description:GATA-3 is a proto-oncogene in T-cell lymphoproliferative neoplasms.
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Project description:Oncogene-induced senescence (OIS) is a tumor suppression mechanism that blocks cell proliferation in response to oncogenic signalling. OIS is frequently accompanied by multinucleation; however, the origin of this is unknown. Here we show that multinucleate OIS cells originated mostly from failed mitosis. Prior to senescence, mutant RasV12 activation in primary human fibroblasts compromised mitosis, associated with abnormal expression of mitotic genes that enter M-phase. Simultaneously, RasV12 activation enhanced survival of damaged mitoses, culminating in extended mitotic arrest and aberrant exit from mitosis via mitotic slippage. ERK-dependent transcriptional up-regulation of Mcl1 was responsible for enhanced slippage of cells with mitotic defects and subsequent cell survival. Importantly, mitotic slippage and oncogene signalling synergistically induced senescence and key senescence regulators p21 and p16. We propose that activated Ras induces transcriptional changes that predispose cells undergoing OIS to mitotic stress and multinucleation. We used RNA-seq of IMR90 cells with inducible expression of oncogenic RasV12 that were synchronised in mitosis, to characterise the nature of mitotic defects that lead to multinucleation of oncogene-induced senescent cells
2015-08-13 | E-GEOD-70668 | biostudies-arrayexpress
Project description:GATA-3 is a proto-oncogene in T-cell lymphoproliferative neoplasms [ChIP-seq]
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Project description:Mutations such as gene fusion, translocation and focal amplification are a frequent cause of proto-oncogene activation during tumorigenesis, but such mutations do not explain all cases of proto-oncogene activation. Here we show that disruption of local chromosome conformation can also activate proto-oncogenes in human cells. We mapped chromosome structures in T-cell acute lymphoblastic leukemia (T-ALL), and found that active oncogenes and silent proto-oncogenes generally occur within insulated neighborhoods formed by the looping of two interacting CTCF sites co-occupied by cohesin. Recurrent microdeletions frequently overlap neighborhood boundary sites in T-ALL genomes, and we demonstrate that site-specific perturbation of loop boundaries is sufficient to activate the respective proto-oncogenes in non-malignant cells. We found somatic genomic rearrangements affecting loop boundaries in many cancers. These results suggest that chromosome structural organization is fundamental to identify functional somatic alterations in cancer genomes.
2016-01-23 | GSE77142 | GEO