Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome.
Erin M ParryIgnaty LeshchinerRomain GuiezeConnor JohnsonEugen TauschSameer A ParikhCamilla K LemvighJulien BroseusSebastien HergalantConor MesserFilippo UtroChaya LevovitzKahn RhrissorrakraiLiang LiDaniel RosebrockShanye YinStephanie L DengKara SlowikRaquel JacobsTeddy HuangShuqiang LiGeoffrey G FellRobert A ReddZiao LinBinyamin Asher KnisbacherDimitri LivitzChristof SchneiderNeil RuthenLiudmila ElaginaAmaro Taylor-WeinerBria PersaudAina Z MartinezStacey M FernandesNoelia PurroyAnnabelle J AnandappaJialin MaJulian M HessLaura Z RassentiThomas J KippsNitin JainWilliam G WierdaFlorence CymbalistaPierre FeugierNeil E KayKenneth J LivakBrian P DanyshChip StewartDonna S NeubergMatthew S DavidsJennifer R BrownLaxmi ParidaStephan StilgenbauerGad A GetzCatherine J WuPublished in: Nature medicine (2023)
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 dysregulated in RS versus CLL, and detected clonal evolution of transformation at single-cell resolution, identifying intermediate cell states. Our study defines distinct molecular subtypes of RS and highlights cell-free DNA analysis as a potential tool for early diagnosis and monitoring.