Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome

Erin M. Parry; Ignaty Leshchiner; Romain Guièze; Connor Johnson; Eugen Tausch; Sameer A. Parikh; Camilla Lemvigh; Julien Broséus; Sébastien Hergalant; Conor Messer; Filippo Utro; Chaya Levovitz; Kahn Rhrissorrakrai; Liang Li; Daniel Rosebrock; Shanye Yin; Stephanie Deng; Kara Slowik; Raquel 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 Martinez; Stacey M. Fernandes; Noelia Purroy; Annabelle J. Anandappa; Jialin Ma; Julian Hess; Laura Z. Rassenti; Thomas J. Kipps; Nitin Jain; William 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

doi:10.1038/s41591-022-02113-6

Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome

Erin M. Parry, Ignaty Leshchiner, Romain Guièze, Connor Johnson, Eugen Tausch, Sameer A. Parikh, Camilla Lemvigh, Julien Broséus, Sébastien Hergalant, Conor Messer, Filippo Utro, Chaya Levovitz, Kahn Rhrissorrakrai, Liang Li, Daniel Rosebrock, Shanye Yin, Stephanie Deng, Kara Slowik, Raquel Jacobs, Teddy HuangShuqiang Li, Geoff Fell, Robert Redd, Ziao Lin, Binyamin A. Knisbacher, Dimitri Livitz, Christof Schneider, Neil Ruthen, Liudmila Elagina, Amaro Taylor-Weiner, Bria Persaud, Aina Martinez, Stacey M. Fernandes, Noelia Purroy, Annabelle J. Anandappa, Jialin Ma, Julian Hess, Laura Z. Rassenti, Thomas J. Kipps, Nitin Jain, William 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

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	158-169
Number of pages	12
Journal	Nature Medicine
Volume	29
Issue number	1
DOIs	https://doi.org/10.1038/s41591-022-02113-6
State	Published - Jan 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding

We thank C. Hahn, E. Ten Hacken, W. Zhang, S. Gohil and L. Werner for helpful discussions. We thank C. Patterson, S. Pollock, O. Olive, C. J. Shaughnessy, F. Dao and H. Lyon for assistance in data collection and organization and S. Belkin and C. Birger for assistance in data storage. We thank T. Lehmberg, M. McDonough, C. Galler and M. Collins for assistance in sample collection and biobanking. We thank the patients, their families and the investigators of the clinical trials for providing samples and clinical data. This study was supported by NIH/NCI P01 CA206978 (to C.J.W. and G.G.) and NCI (1U10CA180861-01) (to C.J.W.). The work is partially supported by the Broad/IBM Cancer Resistance Research Project (I.L., G.G. and L.P.) and a grant from Force Hemato (R.G.). Individual support was provided by DDCF Physician-Scientist Fellowship (E.M.P.), Dana-Farber Flames FLAIR fellowship (E.M.P.), ASCO Conquer Cancer Young Investigator Award (E.M.P.), Fishman Family Fund (R.G. and C.L.), EMBO fellowship ALTF 14-2018 (B.A.K.), NCI Research Specialist Award R50CA251956 (S.L.) and NIH/NCI R21CA267527-01 (S.Y.). Additional research support was provided by NIH R01 CA213442 (J.R.B.), Melton Family Foundation (J.R.B.), NIH/NCI R01-CA236361 (T.J.K.) and the Deutsche Forschungsgemeinschaft (DFG) SFB1074 subprojects B10 (E.T.) and subprojects B1 and B2 (E.T., C.S. and S.S.)

Funders	Funder number
ASCO Conquer Cancer
Dana-Farber Flames
Fishman Family Fund
Force Hemato
Melton Family Foundation	R01-CA236361
National Institutes of Health
National Cancer Institute	P01 CA206978, 1U10CA180861-01
Doris Duke Charitable Foundation
European Molecular Biology Organization	R50CA251956, ALTF 14-2018, R21CA267527-01, R01 CA213442
Deutsche Forschungsgemeinschaft	SFB1074

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Parry, E. M., Leshchiner, I., Guièze, R., Johnson, C., Tausch, E., Parikh, S. A., Lemvigh, C., Broséus, J., Hergalant, S., Messer, C., Utro, F., Levovitz, C., Rhrissorrakrai, K., Li, L., Rosebrock, D., Yin, S., Deng, S., Slowik, K., Jacobs, R., ... Wu, C. J. (2023). Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome. Nature Medicine, 29(1), 158-169. https://doi.org/10.1038/s41591-022-02113-6

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title = "Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome",

abstract = "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.",

author = "Parry, {Erin M.} and Ignaty Leshchiner and Romain Gui{\`e}ze and Connor Johnson and Eugen Tausch and Parikh, {Sameer A.} and Camilla Lemvigh and Julien Bros{\'e}us and S{\'e}bastien Hergalant and Conor Messer and Filippo Utro and Chaya Levovitz and Kahn Rhrissorrakrai and Liang Li and Daniel Rosebrock and Shanye Yin and Stephanie Deng and Kara Slowik and Raquel Jacobs and Teddy Huang and Shuqiang Li and Geoff Fell and Robert Redd and Ziao Lin and Knisbacher, {Binyamin A.} and Dimitri Livitz and Christof Schneider and Neil Ruthen and Liudmila Elagina and Amaro Taylor-Weiner and Bria Persaud and Aina Martinez and Fernandes, {Stacey M.} and Noelia Purroy and Anandappa, {Annabelle J.} and Jialin Ma and Julian Hess and Rassenti, {Laura Z.} and Kipps, {Thomas J.} and Nitin Jain and William Wierda and Florence Cymbalista and Pierre Feugier and Kay, {Neil E.} and Livak, {Kenneth J.} and Danysh, {Brian P.} and Chip Stewart and Donna Neuberg and Davids, {Matthew S.} and Brown, {Jennifer R.} and Laxmi Parida and Stephan Stilgenbauer and Gad Getz and Wu, {Catherine J.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = jan,

doi = "10.1038/s41591-022-02113-6",

language = "אנגלית",

volume = "29",

pages = "158--169",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

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}

Parry, EM, Leshchiner, I, Guièze, R, Johnson, C, Tausch, E, Parikh, SA, Lemvigh, C, Broséus, J, Hergalant, S, Messer, C, Utro, F, Levovitz, C, Rhrissorrakrai, K, Li, L, Rosebrock, D, Yin, S, Deng, S, Slowik, K, Jacobs, R, Huang, T, Li, S, Fell, G, Redd, R, Lin, Z, Knisbacher, BA, Livitz, D, Schneider, C, Ruthen, N, Elagina, L, Taylor-Weiner, A, Persaud, B, Martinez, A, Fernandes, SM, Purroy, N, Anandappa, AJ, Ma, J, Hess, J, Rassenti, LZ, Kipps, TJ, Jain, N, Wierda, W, Cymbalista, F, Feugier, P, Kay, NE, Livak, KJ, Danysh, BP, Stewart, C, Neuberg, D, Davids, MS, Brown, JR, Parida, L, Stilgenbauer, S, Getz, G & Wu, CJ 2023, 'Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome', Nature Medicine, vol. 29, no. 1, pp. 158-169. https://doi.org/10.1038/s41591-022-02113-6

TY - JOUR

T1 - Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome

AU - Parry, Erin M.

AU - Leshchiner, Ignaty

AU - Guièze, Romain

AU - Johnson, Connor

AU - Tausch, Eugen

AU - Parikh, Sameer A.

AU - Lemvigh, Camilla

AU - Broséus, Julien

AU - Hergalant, Sébastien

AU - Messer, Conor

AU - Utro, Filippo

AU - Levovitz, Chaya

AU - Rhrissorrakrai, Kahn

AU - Li, Liang

AU - Rosebrock, Daniel

AU - Yin, Shanye

AU - Deng, Stephanie

AU - Slowik, Kara

AU - Jacobs, Raquel

AU - Huang, Teddy

AU - Li, Shuqiang

AU - Fell, Geoff

AU - Redd, Robert

AU - Lin, Ziao

AU - Knisbacher, Binyamin A.

AU - Livitz, Dimitri

AU - Schneider, Christof

AU - Ruthen, Neil

AU - Elagina, Liudmila

AU - Taylor-Weiner, Amaro

AU - Persaud, Bria

AU - Martinez, Aina

AU - Fernandes, Stacey M.

AU - Purroy, Noelia

AU - Anandappa, Annabelle J.

AU - Ma, Jialin

AU - Hess, Julian

AU - Rassenti, Laura Z.

AU - Kipps, Thomas J.

AU - Jain, Nitin

AU - Wierda, William

AU - Cymbalista, Florence

AU - Feugier, Pierre

AU - Kay, Neil E.

AU - Livak, Kenneth J.

AU - Danysh, Brian P.

AU - Stewart, Chip

AU - Neuberg, Donna

AU - Davids, Matthew S.

AU - Brown, Jennifer R.

AU - Parida, Laxmi

AU - Stilgenbauer, Stephan

AU - Getz, Gad

AU - Wu, Catherine J.

PY - 2023/1

Y1 - 2023/1

N2 - 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.

AB - 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.

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AN - SCOPUS:85145920664

SN - 1078-8956

VL - 29

SP - 158

EP - 169

JO - Nature Medicine

JF - Nature Medicine

IS - 1

ER -

Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome

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