作者
Erin M. Parry,Ignaty Leshchiner,Romain Guiéze,Connor Johnson,Eugen Tausch,Sameer A. Parikh,Camilla K. Lemvigh,Julien Broséus,Sébastien Hergalant,Conor Messer,Filippo Utro,Chaya Levovitz,Kahn Rhrissorrakrai,Liang Li,Daniel Rosebrock,Shanye Yin,Stephanie Deng,Kara Slowik,Raquel A. Jacobs,Teddy Huang,Shuqiang Li,Geoff Fell,Robert Redd,Ziao Lin,Binyamin A. Knisbacher,Dimitri Livitz,Christof Schneider,Neil Ruthen,Liudmila Elagina,Amaro Taylor‐Weiner,Bria Persaud,Aina Zurita Martinez,Stacey M. Fernandes,Noelia Purroy,Annabelle Anandappa,Jialin Ma,Julian M. Hess,Laura Z. Rassenti,Thomas J. Kipps,Nitin Jain,William G. Wierda,Florence Cymbalista,Pierre Feugier,Neil E. Kay,Kenneth J. Livak,Brian P. Danysh,Chip Stewart,Donna Neuberg,Matthew S. Davids,Jennifer R. Brown,Laxmi Parida,Stephan Stilgenbauer,Gad Getz,Catherine J. Wu
摘要
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. Integrative genomic and transcriptomic analyses reveal molecular events defining Richter transformation from CLL, and highlight the potential of cell-free DNA for early detection.