Omics · study · 2026
Altered spindle assembly checkpoint function impairs B cell development but drives their early transformation.
Listed in NCBI GEO
Chromosomal instability (CIN) is an established driver of aneuploidy and malignant disease, yet also known to reduce cellular fitness, promoting cell cycle arrest or cell death.
Description
These checks and balances need to be overcome during malignant transformation. Here, we investigate the role of apoptosis as a consequence of CIN and barrier against aneuploidy in the context of white blood cell development and their transformation by impairing the spindle assembly checkpoint (SAC) function specifically in B lymphocytes.
We found that loss of the mitotic check-point complex component Mad2l1 was incompatible with B cell development nor their oncogenic transformation. In contrast, SAC impairment caused by a truncation mutation in MPS1 kinase led to a partial block in B cell development and lymphopenia. A genome-wide loss-of-function screen identified reduced B cell output to be due to BCL2-regulated mitochondrial apoptosis involving the pro-apoptotic BH3-only proteins, BIM/BCL2L11 and PUMA/BBC3.
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Impairment of MPS1 kinase activity failed to promote cancer on its own, but strongly synergized with oncogenic MYC or p53-deficiency in B cell transformation. In contrast, apoptosis inhibition by BCL2 overexpression in combination with recued MPS1 function was insufficient to promote disease. Hence, impairment of apoptotic cell death alone, while partially restoring B cell development in the presence of reduced SAC function, is insufficient to facilitate transformation.
Together, these findings suggest that cell death drives the rapid selection of karyotypes that adapt to SAC perturbation. As such, apoptosis fails to act as a barrier against CIN-driven B lymphomagenesis and BCL2 regulated cell death facilitates the formation of B cell malignancies in cells experiencing chronic CIN.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE313nnn/GSE313024 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE313024 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1378142 ncbi.nlm.nih.gov/bioproject/PRJNA1378142 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Mus musculus
- From keywords
- Life Sciences
Provenance · 1 source records, 10 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE313024 | 13 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:cancer | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[disease].local:disease:disease | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].anzsrc:group:3105 | enrichment · NCBI GEO | taxonomy-embedding@1.1.0 | title+keywords+description (69%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[organism].NCBITaxon:10090 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |