{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T04:52:46Z","timestamp":1777611166271,"version":"3.51.4"},"reference-count":49,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T00:00:00Z","timestamp":1721779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/genes15080978","type":"journal-article","created":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T08:40:04Z","timestamp":1721896804000},"page":"978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of Gene Regulatory Networks in B-Cell Progenitor Differentiation and Leukemia"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4431-8988","authenticated-orcid":false,"given":"Stefan","family":"Nagel","sequence":"first","affiliation":[{"name":"Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, 38124 Braunschweig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corinna","family":"Meyer","sequence":"additional","affiliation":[{"name":"Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, 38124 Braunschweig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.cell.2018.09.045","article-title":"The Human Transcription Factors","volume":"175","author":"Lambert","year":"2018","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nrg2538","article-title":"A census of human transcription factors: Function, expression and evolution","volume":"10","author":"Vaquerizas","year":"2009","journal-title":"Nat. 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