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Molecular map of chronic lymphocytic leukemia and its impact on outcome

dc.contributor.authorKnisbacher, B. A.
dc.contributor.authorLin, Z.
dc.contributor.authorHahn, C. K.
dc.contributor.authorBousquets Muñoz, Pablo 
dc.contributor.authorDíaz Navarro, Ander 
dc.contributor.authorLópez Tamargo, Sara 
dc.contributor.authorSuárez Puente, Xosé Antón
dc.identifier.citationNature Genetics, 54(11), p. 1664-1674 (2022); doi:10.1038/s41588-022-01140-w
dc.description.abstractRecent 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.
dc.description.sponsorshipThis 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.
dc.description.statementofresponsibilityKnisbacher, 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., Sivina, M., Rassenti, L.Z., Schneider, C., Li, S., Parida, L., Meissner, A., Aguet, F., Burger, J.A., Wiestner, A., Kipps, T.J., Brown, J.R., Hallek, M., Stewart, C., Neuberg, D.S., Martín-Subero, J.I., Puente, X.S., Stilgenbauer, S., Wu, C.J., Campo, E., Getz, G.
dc.format.extentp. 1664-1674
dc.relation.ispartofNature Genetics
dc.titleMolecular map of chronic lymphocytic leukemia and its impact on outcome
dc.typejournal article

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