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Identification of Gene Regulatory Networks in B-Cell Progenitor Differentiation and Leukemia.
- Source :
- Genes; Aug2024, Vol. 15 Issue 8, p978, 15p
- Publication Year :
- 2024
-
Abstract
- Pro-B- and pre-B-cells are consecutive entities in early B-cell development, representing cells of origin for B-cell precursor acute lymphoid leukemia (BCP-ALL). Normal B-cell differentiation is critically regulated by specific transcription factors (TFs). Accordingly, TF-encoding genes are frequently deregulated or mutated in BCP-ALL. Recently, we described TF-codes which delineate physiological activities of selected groups of TF-encoding genes in hematopoiesis including B-cell development. Here, we exploited these codes to uncover regulatory connections between particular TFs in pro-B- and pre-B-cells via an analysis of developmental TFs encoded by NKL and TALE homeobox genes and by ETS and T-box genes. Comprehensive expression analyses in BCP-ALL cell lines helped identify validated models to study their mutual regulation in vitro. Knockdown and overexpression experiments and subsequent RNA quantification of TF-encoding genes in selected model cell lines revealed activating, inhibitory or absent connections between nine TFs operating in early B-cell development, including HLX, MSX1, IRX1, MEIS1, ETS2, ERG, SPIB, EOMES, and TBX21. In addition, genomic profiling revealed BCP-ALL subtype-specific copy number alterations of ERG at 21q22, while a deletion of the TGFbeta-receptor gene TGFBR2 at 3p24 resulted in an upregulation of EOMES. Finally, we combined the data to uncover gene regulatory networks which control normal differentiation of early B-cells, collectively endorsing more detailed evaluation of BCP-ALL subtypes. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 20734425
- Volume :
- 15
- Issue :
- 8
- Database :
- Complementary Index
- Journal :
- Genes
- Publication Type :
- Academic Journal
- Accession number :
- 179353991
- Full Text :
- https://doi.org/10.3390/genes15080978