{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:43:00Z","timestamp":1792795380682,"version":"4.5.0"},"reference-count":70,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T00:00:00Z","timestamp":1730764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries and it can progress to Richter\u2019s syndrome (RS), a more aggressive condition. The NF-\u03baB pathway is pivotal in CLL pathogenesis, driven mainly by B-cell receptor (BCR) signaling. However, recent evidence indicates that BCR signaling is reduced in RS, raising questions about whether and how NF-\u03baB activity is maintained in RS. This study aims to elucidate the triggers and dynamics of NF-\u03baB activation and the progression from CLL to RS. Methods: Integrated single-cell RNA sequencing data from peripheral blood samples of four CLL\u2013RS patients were analyzed. NF-\u03baB pathway activity and gene expression profiles were assessed to determine changes in NF-\u03baB components and their targets. Tumor microenvironment composition and cell\u2013cell communication patterns were inferred to explore NF-\u03baB regulatory mechanisms. Results: RS samples showed increased proportions of malignant cells expressing NF-\u03baB components, including NFKB1, NFKB2, RELA, IKBKG, MAP3K14, CHUK, and IKBKB, with significantly higher expression levels than in CLL. Enhanced NF-\u03baB pathway activity in RS cells was associated with targets involved in immune modulation. The tumor microenvironment in RS displayed significant compositional changes, and signaling inference revealed enhanced cell\u2013cell communication via BAFF and APRIL pathways, involving interactions with receptors such as BAFF-R and TACI on RS cells. Conclusions: The findings from this study reveal an active state of NF-\u03baB in RS and suggest that this state plays a critical role in the evolution of CLL to RS, which is modulated by alternative signaling pathways and the influence of the tumor microenvironment.<\/jats:p>","DOI":"10.3390\/genes15111434","type":"journal-article","created":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T05:30:53Z","timestamp":1730784653000},"page":"1434","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["NF-\u039aB Activation as a Key Driver in Chronic Lymphocytic Leukemia Evolution to Richter\u2019s Syndrome: Unraveling the Influence of Immune Microenvironment Dynamics"],"prefix":"10.3390","volume":"15","author":[{"given":"Paulo","family":"Rohan","sequence":"first","affiliation":[{"name":"Stem Cell Laboratory, Specialized Laboratories Division, Instituto Nacional de C\u00e2ncer (INCA), Rio de Janeiro 20230-130, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7590-0335","authenticated-orcid":false,"given":"Renata","family":"Binato","sequence":"additional","affiliation":[{"name":"Stem Cell Laboratory, Specialized Laboratories Division, Instituto Nacional de C\u00e2ncer (INCA), Rio de Janeiro 20230-130, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5166-0832","authenticated-orcid":false,"given":"Eliana","family":"Abdelhay","sequence":"additional","affiliation":[{"name":"Stem Cell Laboratory, Specialized Laboratories Division, Instituto Nacional de C\u00e2ncer (INCA), Rio de Janeiro 20230-130, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1159\/000533610","article-title":"Chronic Lymphocytic Leukemia: Disease Biology","volume":"147","author":"Koehrer","year":"2023","journal-title":"Acta Haematol."},{"key":"ref_2","unstructured":"Mukkamalla, S.K.R., Taneja, A., Malipeddi, D., and Master, S.R. 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