Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
01 2023
01 2023
Historique:
received:
23
12
2021
accepted:
28
10
2022
pubmed:
10
1
2023
medline:
27
1
2023
entrez:
9
1
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36624313
doi: 10.1038/s41591-022-02113-6
pii: 10.1038/s41591-022-02113-6
pmc: PMC10155825
mid: NIHMS1882397
doi:
Substances chimiques
SRSF1 protein, human
0
Serine-Arginine Splicing Factors
170974-22-8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
158-169Subventions
Organisme : NCI NIH HHS
ID : U10 CA180861
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA270085
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG002295
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA236361
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA015083
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA251956
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA267527
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA206978
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213442
Pays : United States
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
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