biostudies-literatureParry EMNHGRI NIH HHSNCI NIH HHS158-169https://www.ebi.ac.uk/biostudies/studies/S-EPMC10155825biostudies-literatureUnknown29(1)Richter syndrome (RS) arising from chronic lymphocytic leukemia (CLL) exemplifies an aggressive malignancy that develops from an indolent neoplasm. To decipher the genetics underlying this transformation, we computationally deconvoluted admixtures of CLL and RS cells from 52 patients with RS, evaluating paired CLL-RS whole-exome sequencing data. We discovered RS-specific somatic driver mutations (including IRF2BP2, SRSF1, B2M, DNMT3A and CCND3), recurrent copy-number alterations beyond del(9p21)(CDKN2A/B), whole-genome duplication and chromothripsis, which were confirmed in 45 independent RS cases and in an external set of RS whole genomes. Through unsupervised clustering, clonally related RS was largely distinct from diffuse large B cell lymphoma. We distinguished pathways that were dysreNature medicineEvolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome.PMC10155825K08 CA270085R21 CA267527P30 CA015083R50 CA251956U10 CA180861R01 CA236361P01 CA206978T32 HG002295R01 CA213442Deng SHess JLin ZElagina LParikh SALivak KJBroseus JStewart CRuthen NLivitz DSlowik KJain NKipps TJPurroy NCymbalista FLevovitz CLi LKnisbacher BARedd RBrown JRFell GNeuberg DLi SWu CJMartinez ADanysh BPRhrissorrakrai KKay NEUtro FDavids MSGetz GLeshchiner IJacobs RHergalant SWierda WSchneider CRassenti LZJohnson CParry EMFernandes SMGuieze RYin SParida LLemvigh CHuang TFeugier PPersaud BTaylor-Weiner AMesser CMa JTausch EStilgenbauer SAnandappa AJRosebrock DfalseEvolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome.Richter syndrome (RS) arising from chronic lymphocytic leukemia (CLL) exemplifies an aggressive malignancy that develops from an indolent neoplasm. To decipher the genetics underlying this transformation, we computationally deconvoluted admixtures of CLL and RS cells from 52 patients with RS, evaluating paired CLL-RS whole-exome sequencing data. We discovered RS-specific somatic driver mutations (including IRF2BP2, SRSF1, B2M, DNMT3A and CCND3), recurrent copy-number alterations beyond del(9p21)(CDKN2A/B), whole-genome duplication and chromothripsis, which were confirmed in 45 independent RS cases and in an external set of RS whole genomes. Through unsupervised clustering, clonally related RS was largely distinct from diffuse large B cell lymphoma. We distinguished pathways that were dysre2023-01-01T00:00:00Z2023 Jan2026-05-28T12:22:25.789Z2025-04-07T10:25:11.309ZS-EPMC101558253662431310.1038/s41591-022-02113-6