Molecular map of chronic lymphocytic leukemia and its impact on outcome

Binyamin A. Knisbacher; Ziao Lin; Cynthia K. Hahn; Ferran Nadeu; Martí Duran-Ferrer; Kristen E. Stevenson; Eugen Tausch; Julio Delgado; Alex Barbera-Mourelle; Amaro Taylor-Weiner; Pablo Bousquets-Muñoz; Ander Diaz-Navarro; Andrew Dunford; Shankara Anand; Helene Kretzmer; Jesus Gutierrez-Abril; Sara López-Tamargo; Stacey M. Fernandes; Clare Sun; Mariela Sivina; Laura Z. Rassenti; Christof Schneider; Shuqiang Li; Laxmi Parida; Alexander Meissner; François Aguet; Jan A. Burger; Adrian Wiestner; Thomas J. Kipps; Jennifer R. Brown; Michael Hallek; Chip Stewart; Donna S. Neuberg; José I. Martín-Subero; Xose S. Puente; Stephan Stilgenbauer; Catherine J. Wu; Elias Campo; Gad Getz

doi:10.1038/s41588-022-01140-w

Molecular map of chronic lymphocytic leukemia and its impact on outcome

Binyamin A. Knisbacher, Ziao Lin, Cynthia K. Hahn, Ferran Nadeu, Martí Duran-Ferrer, Kristen E. Stevenson, Eugen Tausch, Julio Delgado, Alex Barbera-Mourelle, Amaro Taylor-Weiner, Pablo Bousquets-Muñoz, Ander Diaz-Navarro, Andrew Dunford, Shankara Anand, Helene Kretzmer, Jesus Gutierrez-Abril, Sara López-Tamargo, Stacey M. Fernandes, Clare Sun, Mariela SivinaLaura Z. Rassenti, Christof Schneider, Shuqiang Li, Laxmi Parida, Alexander Meissner, François Aguet, Jan A. Burger, Adrian Wiestner, Thomas J. Kipps, Jennifer R. Brown, Michael Hallek, Chip Stewart, Donna S. Neuberg, José I. Martín-Subero, Xose S. Puente, Stephan Stilgenbauer, Catherine J. Wu, Elias Campo, Gad Getz

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

67 Scopus citations

Abstract

Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the ‘CLL map,’ we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication.

Original language	English
Pages (from-to)	1664-1674
Number of pages	11
Journal	Nature Genetics
Volume	54
Issue number	11
DOIs	https://doi.org/10.1038/s41588-022-01140-w
State	Published - Nov 2022
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding

We thank W. Zhang, S. Gohil, I. Leshchiner, D. Livitz, D. Rosebrock, J. Gribben, K. R. Rai, M. J. Keating, J. M. Hess, N. J. Haradhvala, A. Mohammed and A. Gnirke for helpful discussions. We thank C. Patterson, S. Pollock, K. Slowik, O. Olive, C. J. Shaughnessy and H. Lyon for assistance in data collection and organization. We thank the patients, their families and the investigators of the clinical trials for providing samples and clinical data. This study was supported by National Institutes of Health (NIH)/National Cancer Institute (NCI) grant P01 CA206978 (to C.J.W. and G.G.) and the Broad/IBM Cancer Resistance Research Project (G.G. and L.P.). B.A.K. was supported by a long-term EMBO fellowship (ALTF 14-2018). C.K.H. was supported by the NHLBI Training Program in Molecular Hematology (T32HL116324). F.N. acknowledges funding by the American Association for Cancer Research (2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research, 21-40-11-NADE), the European Hematology Association (EHA Junior Research Grant 2021, RG-202012-00245), and the Lady Tata Memorial Trust (International Award for Research in Leukaemia 2021-2022, LADY_TATA_21_3223). S.S. and E.T. were supported by the Deutsche Forschungsgemeinschaft (SFB1074, subproject B1, B2 and B10). A.W. and C. Sun were supported by the Intramural Research Program at NIH/NHLBI. J.A.B. was supported by MD Anderson’s Moon Shot Program in CLL and the CLL Global Research Foundation and in part by MDACC Support Grant CA016672. S.L. was supported by the NCI Research Specialist Award (R50CA251956). J.R.B. was supported by NIH grant R01 CA 213442, NIH/NCI grant P01 CA206978 and the Melton Family Foundation. X.S.P. acknowledges funding by the Spanish Ministerio de Economía y Competitividad (grants SAF2017-87811-R and PID2020-117185RB-I00). A.D.-N. was supported by the Department of Education of the Basque Government (PRE_2017_1_0100) and P.B.-M. by a fellowship by the Spanish Ministerio de Economía y Competitividad. This study was supported by “la Caixa” Foundation (CLLEvolution- LCF/PR/HR17/52150017, Health Research 2017 Program “HR17-0022” to E.C.), the European Research Council under the European Union’s Horizon 2020 research and innovation program (Project BCLLATLAS, grant agreement 810287) (to J.I.M.-S. and E.C.), the Accelerator award CRUK/AIRC/AECC joint funder-partnership (to J.I.M.-S.), Generalitat de Catalunya Suport Grups de Recerca AGAUR 2017-SGR-1142 (to E.C.) and 2017-SGR-736 (to J.I.M.-S.), CERCA Programme/Generalitat de Catalunya. E.C. is an Academia Researcher of Catalan Institution for Research and Advanced Studies. We thank W. Zhang, S. Gohil, I. Leshchiner, D. Livitz, D. Rosebrock, J. Gribben, K. R. Rai, M. J. Keating, J. M. Hess, N. J. Haradhvala, A. Mohammed and A. Gnirke for helpful discussions. We thank C. Patterson, S. Pollock, K. Slowik, O. Olive, C. J. Shaughnessy and H. Lyon for assistance in data collection and organization. We thank the patients, their families and the investigators of the clinical trials for providing samples and clinical data. This study was supported by National Institutes of Health (NIH)/National Cancer Institute (NCI) grant P01 CA206978 (to C.J.W. and G.G.) and the Broad/IBM Cancer Resistance Research Project (G.G. and L.P.). B.A.K. was supported by a long-term EMBO fellowship (ALTF 14-2018). C.K.H. was supported by the NHLBI Training Program in Molecular Hematology (T32HL116324). F.N. acknowledges funding by the American Association for Cancer Research (2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research, 21-40-11-NADE), the European Hematology Association (EHA Junior Research Grant 2021, RG-202012-00245), and the Lady Tata Memorial Trust (International Award for Research in Leukaemia 2021-2022, LADY_TATA_21_3223). S.S. and E.T. were supported by the Deutsche Forschungsgemeinschaft (SFB1074, subproject B1, B2 and B10). A.W. and C. Sun were supported by the Intramural Research Program at NIH/NHLBI. J.A.B. was supported by MD Anderson’s Moon Shot Program in CLL and the CLL Global Research Foundation and in part by MDACC Support Grant CA016672. S.L. was supported by the NCI Research Specialist Award (R50CA251956). J.R.B. was supported by NIH grant R01 CA 213442, NIH/NCI grant P01 CA206978 and the Melton Family Foundation. X.S.P. acknowledges funding by the Spanish Ministerio de Economía y Competitividad (grants SAF2017-87811-R and PID2020-117185RB-I00). A.D.-N. was supported by the Department of Education of the Basque Government (PRE_2017_1_0100) and P.B.-M. by a fellowship by the Spanish Ministerio de Economía y Competitividad. This study was supported by “la Caixa” Foundation (CLLEvolution- LCF/PR/HR17/52150017, Health Research 2017 Program “HR17-0022” to E.C.), the European Research Council under the European Union’s Horizon 2020 research and innovation program (Project BCLLATLAS, grant agreement 810287) (to J.I.M.-S. and E.C.), the Accelerator award CRUK/AIRC/AECC joint funder-partnership (to J.I.M.-S.), Generalitat de Catalunya Suport Grups de Recerca AGAUR 2017-SGR-1142 (to E.C.) and 2017-SGR-736 (to J.I.M.-S.), CERCA Programme/Generalitat de Catalunya. E.C. is an Academia Researcher of Catalan Institution for Research and Advanced Studies. The authors declare the following conflicts related to the CLLmap project: C.J.W. receives research support from Pharmacyclics. E.C. has been a consultant for Illumina. G.G. receives research funds from IBM and Pharmacyclics; and is an inventor on patent applications related to SignatureAnalyzer-GPU. S.S. reports honoraria for consultancy, advisory board membership, speaker honoraria, research grants and travel support from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis. C.J.W., G.G., B.A.K., Z.L. and C.K.H. are inventors on a patent “Compositions, panels, and methods for characterizing chronic lymphocytic leukemia” (PCT/US21/45144). The following conflicts are unrelated to the CLLmap project: F.N. has received honoraria from Janssen for speaking at educational activities. E.T. declares research support by AbbVie and Roche; Advisory Boards and Speakers Bureau for Janssen, AbbVie and Roche. A.W. received research funding from Pharmacyclics, Acerta, Merck, Verastem, Genmab, Nurix. J.R.B. has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Novartis, Pfizer, Rigel; received research funding from Gilead, Loxo/Lilly, Verastem/SecuraBio, Sun, TG Therapeutics; and served on the data safety monitoring committee for Invectys. J.A.B. received research support from AstraZeneca, BeiGene, Gilead, and Pharmacyclics; travel and speaker honoraria from Janssen. X.S.P. is a cofounder of and holds an equity stake in DREAMgenics. C.J.W. holds equity in BioNTech, Inc.. E.C. has been a consultant for Takeda and NanoString Technologies; has received honoraria from Janssen and Roche for speaking at educational activities; and is an inventor on a Lymphoma and Leukemia Molecular Profiling Project patent “Method for subtyping lymphoma subtypes by means of expression profiling” (PCT/US2014/64161). G.G. is an inventor on patent applications related to MSMuTect, MSMutSig, MSIDetect and POLYSOLVER; and is a founder and consultant of and holds privately held equity in Scorpion Therapeutics. The other authors declare no competing interests.

Funders	Funder number
Department of Education of the Basque Government	PRE_2017_1_0100
Generalitat de Catalunya Suport Grups de Recerca AGAUR	2017-SGR-1142, 2017-SGR-736
MDACC	CA016672, R01 CA 213442
Melton Family Foundation
Pharmacyclics, Acerta, Merck
de Catalunya
National Institutes of Health
American Association for Cancer Research	21-40-11-NADE
National Heart, Lung, and Blood Institute	ZIAHL002346, T32HL116324
National Cancer Institute	R50CA251956, P01 CA206978
GlaxoSmithKline
European Molecular Biology Organization	ALTF 14-2018
Gilead Sciences
CLL Global Research Foundation
F. Hoffmann-La Roche
Albert Einstein Cancer Center
European Hematology Association
Janssen Pharmaceuticals
“la Caixa” Foundation	HR17-0022, CLLEvolution- LCF/PR/HR17/52150017
Horizon 2020 Framework Programme	810287
EcoHealth Alliance	RG-202012-00245
Cancer Research UK
European Commission
Deutsche Forschungsgemeinschaft	B10, SFB1074
Ministerio de Economía y Competitividad	PID2020-117185RB-I00, SAF2017-87811-R
Lady Tata Memorial Trust	2021-2022, LADY_TATA_21_3223
Associazione Italiana per la Ricerca sul Cancro

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41588-022-01140-w

Cite this

Knisbacher, B. A., Lin, Z., Hahn, C. K., Nadeu, F., Duran-Ferrer, M., Stevenson, K. E., Tausch, E., Delgado, J., Barbera-Mourelle, A., Taylor-Weiner, A., Bousquets-Muñoz, P., Diaz-Navarro, A., Dunford, A., Anand, S., Kretzmer, H., Gutierrez-Abril, J., López-Tamargo, S., Fernandes, S. M., Sun, C., ... Getz, G. (2022). Molecular map of chronic lymphocytic leukemia and its impact on outcome. Nature Genetics, 54(11), 1664-1674. https://doi.org/10.1038/s41588-022-01140-w

@article{5094737c29004c99becda8a5b33e692b,

title = "Molecular map of chronic lymphocytic leukemia and its impact on outcome",

abstract = "Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the {\textquoteleft}CLL map,{\textquoteright} we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication.",

author = "Knisbacher, {Binyamin A.} and Ziao Lin and Hahn, {Cynthia K.} and Ferran Nadeu and Mart{\'i} Duran-Ferrer and Stevenson, {Kristen E.} and Eugen Tausch and Julio Delgado and Alex Barbera-Mourelle and Amaro Taylor-Weiner and Pablo Bousquets-Mu{\~n}oz and Ander Diaz-Navarro and Andrew Dunford and Shankara Anand and Helene Kretzmer and Jesus Gutierrez-Abril and Sara L{\'o}pez-Tamargo and Fernandes, {Stacey M.} and Clare Sun and Mariela Sivina and Rassenti, {Laura Z.} and Christof Schneider and Shuqiang Li and Laxmi Parida and Alexander Meissner and Fran{\c c}ois Aguet and Burger, {Jan A.} and Adrian Wiestner and Kipps, {Thomas J.} and Brown, {Jennifer R.} and Michael Hallek and Chip Stewart and Neuberg, {Donna S.} and Mart{\'i}n-Subero, {Jos{\'e} I.} and Puente, {Xose S.} and Stephan Stilgenbauer and Wu, {Catherine J.} and Elias Campo and Gad Getz",

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Knisbacher, BA, Lin, Z, Hahn, CK, Nadeu, F, Duran-Ferrer, M, Stevenson, KE, Tausch, E, Delgado, J, Barbera-Mourelle, A, Taylor-Weiner, A, Bousquets-Muñoz, P, Diaz-Navarro, A, Dunford, A, Anand, S, Kretzmer, H, Gutierrez-Abril, J, López-Tamargo, S, Fernandes, SM, Sun, C, Sivina, M, Rassenti, LZ, Schneider, C, Li, S, Parida, L, Meissner, A, Aguet, F, Burger, JA, Wiestner, A, Kipps, TJ, Brown, JR, Hallek, M, Stewart, C, Neuberg, DS, Martín-Subero, JI, Puente, XS, Stilgenbauer, S, Wu, CJ, Campo, E & Getz, G 2022, 'Molecular map of chronic lymphocytic leukemia and its impact on outcome', Nature Genetics, vol. 54, no. 11, pp. 1664-1674. https://doi.org/10.1038/s41588-022-01140-w

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AU - Puente, Xose S.

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AB - Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the ‘CLL map,’ we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication.

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Molecular map of chronic lymphocytic leukemia and its impact on outcome

Abstract

Bibliographical note

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