Key processes in the onset and evolution of chronic lymphocytic leukemia (CLL) are thought to include chronic (antigenic) activation of mature B cells through the B cell receptor (BcR), signals from the microenvironment, and acquisition of genetic alterations. Here we describe three families in which two or more siblings were affected by CLL. We investigated whether there are immunogenetic similarities in the leukemia-specific immunoglobulin heavy (IGH) and light (IGL/IGK) chain gene rearrangements of the siblings in each family. Furthermore, we performed array analysis to study if similarities in CLL-associated chromosomal aberrations are present within each family and screened for somatic mutations using paired tumor/normal whole-genome sequencing (WGS). In two families a consistent IGHV gene mutational status (one IGHV-unmutated, one IGHV-mutated) was observed. Intriguingly, the third family with four affected siblings was characterized by usage of the lambda IGLV3-21 gene, with the hallmark R110 mutation of the recently described clinically aggressive IGLV3-21R110 subset. In this family, the CLL-specific rearrangements in two siblings could be assigned to either stereotyped subset #2 or the immunogenetically related subset #169, both of which belong to the broader IGLV3-21R110 subgroup. Consistent patterns of cytogenetic aberrations were encountered in all three families. Furthermore, the CLL clones carried somatic mutations previously associated with IGHV mutational status, cytogenetic aberrations and stereotyped subsets, respectively. From these findings, we conclude that similarities in immunogenetic characteristics in familial CLL, in combination with genetic aberrations acquired, point towards shared underlying mechanisms behind CLL development within each family.

CEITEC Central European Institute of Technology Masaryk University Brno Czechia

Department of Biology School of Science National and Kapodistrian University of Athens Athens Greece

Department of Clinical Genetics Erasmus MC University Medical Center Rotterdam Netherlands

Department of Clinical Genetics Karolinska University Laboratory Karolinska University Hospital Solna Sweden

Department of Hematology University Hospital Schleswig Holstein Kiel Germany

Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Uppsala Sweden

Department of Immunology LUMC Leiden Netherlands

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Pulmonary Medicine Erasmus MC University Medical Center Rotterdam Netherlands

Institute of Applied Biosciences Centre for Research and Technology Hellas Thessaloniki Greece

Laboratory Medical Immunology Department of Immunology Erasmus MC University Medical Center Rotterdam Netherlands

Zobrazit více v PubMed

Hallek M. Chronic Lymphocytic Leukemia: 2020 Update on Diagnosis, Risk Stratification and Treatment. Am J Hematol (2019) 94(11):1266–87. 10.1002/ajh.25595 PubMed DOI

Kipps TJ, Stevenson FK, Wu CJ, Croce CM, Packham G, Wierda WG, et al. . Chronic Lymphocytic Leukaemia. Nat Rev Dis Primers (2017) 3:1–12. 10.1038/nrdp.2016.96 PubMed DOI PMC

Baliakas P, Jeromin S, Iskas M, Puiggros A, Plevova K, Nguyen-Khac F, et al. . Cytogenetic Complexity in Chronic Lymphocytic Leukemia: Definitions, Associations, and Clinical Impact. Blood (2019) 133(11):1205–16. 10.1182/blood-2018-09-873083 PubMed DOI PMC

Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, et al. . Mutations Driving CLL and Their Evolution in Progression and Relapse. Nature (2015) 526(7574):525–30. 10.1038/nature15395 PubMed DOI PMC

Dohner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, et al. . Genomic Aberrations and Survival in Chronic Lymphocytic Leukemia. New Engl J Med (2000) 343(26):1910–6. 10.1056/NEJM200012283432602 PubMed DOI

Klein U, Lia M, Crespo M, Siegel R, Shen Q, Mo T, et al. . The DLEU2/miR-15a/16-1 Cluster Controls B Cell Proliferation and Its Deletion Leads to Chronic Lymphocytic Leukemia. Cancer Cell (2010) 17(1):28–40. 10.1016/j.ccr.2009.11.019 PubMed DOI

Dohner H, Stilgenbauer S, James MR, Benner A, Weilguni T, Bentz M, et al. . 11q Deletions Identify a New Subset of B-Cell Chronic Lymphocytic Leukemia Characterized by Extensive Nodal Involvement and Inferior Prognosis. Blood (1997) 89(7):2516–22. 10.1182/blood.V89.7.2516 PubMed DOI

Guarini A, Marinelli M, Tavolaro S, Bellacchio E, Magliozzi M, Chiaretti S, et al. . ATM Gene Alterations in Chronic Lymphocytic Leukemia Patients Induce a Distinct Gene Expression Profile and Predict Disease Progression. Haematologica (2012) 97(1):47–55. 10.3324/haematol.2011.049270 PubMed DOI PMC

Marinelli M, Peragine N, Di Maio V, Chiaretti S, Stefania De Propris M, Raponi S, et al. . Identification of Molecular and Functional Patterns of P53 Alterations in Chronic Lymphocytic Leukemia Patients in Different Phases of the Disease. Haematologica (2013) 98(3):371–5. 10.3324/haematol.2012.069906 PubMed DOI PMC

Abruzzo LV, Herling CD, Calin GA, Oakes C, Barron LL, Banks HE, et al. . Trisomy 12 Chronic Lymphocytic Leukemia Expresses a Unique Set of Activated and Targetable Pathways. Haematologica (2018) 103(12):2069–78. 10.3324/haematol.2018.190132 PubMed DOI PMC

Roos-Weil D, Nguyen-Khac F, Chevret S, Touzeau C, Roux C, Lejeune J, et al. . Mutational and Cytogenetic Analyses of 188 CLL Patients With Trisomy 12: A Retrospective Study From the French Innovative Leukemia Organization (FILO) Working Group. Genes Chromosomes Cancer (2018) 57(11):533–40. 10.1002/gcc.22650 PubMed DOI

Puente XS, Bea S, Valdes-Mas R, Villamor N, Gutiérrez-Abril J, Martín-Subero JI, et al. . Non-Coding Recurrent Mutations in Chronic Lymphocytic Leukaemia. Nature (2015) 526(7574):519–24. 10.1038/nature14666 PubMed DOI

Ljungstrom V, Cortese D, Young E, Pandzic R, Mansouri L, Plevova K, et al. . Whole-Exome Sequencing in Relapsing Chronic Lymphocytic Leukemia: Clinical Impact of Recurrent RPS15 Mutations. Blood (2016) 127(8):1007–16. 10.1182/blood-2015-10-674572 PubMed DOI PMC

Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K, et al. . SF3B1 and Other Novel Cancer Genes in Chronic Lymphocytic Leukemia. N Engl J Med (2011) 365(26):2497–506. 10.1056/NEJMoa1109016 PubMed DOI PMC

Quesada V, Conde L, Villamor N, Ordóñez GR, Jares P, Bassaganyas L, et al. . Exome Sequencing Identifies Recurrent Mutations of the Splicing Factor SF3B1 Gene in Chronic Lymphocytic Leukemia. Nat Genet (2011) 44(1):47–52. 10.1038/ng.1032 PubMed DOI

Rosenquist R, Ghia P, Hadzidimitriou A, Sutton L-A, Agathangelidis A, Baliakas P, et al. . Immunoglobulin Gene Sequence Analysis in Chronic Lymphocytic Leukemia: Updated ERIC Recommendations. Leukemia (2017) 31(7):1477–81. 10.1038/leu.2017.125 PubMed DOI PMC

Agathangelidis A, Chatzidimitriou A, Gemenetzi K, Giudicelli V, Karypidou M, Plevova K, et al. . Higher-Order Connections Between Stereotyped Subsets: Implications for Improved Patient Classification in CLL. Blood (2021) 137(10):1365–76. 10.1182/blood.2020007039 PubMed DOI PMC

Jaramillo S, Agathangelidis A, Schneider C, Bahlo J, Robrecht S, Tausch E, et al. . Prognostic Impact of Prevalent Chronic Lymphocytic Leukemia Stereotyped Subsets: Analysis Within Prospective Clinical Trials of the German CLL Study Group (GCLLSG). Haematologica (2020) 105(11):2598–607. 10.3324/haematol.2019.231027 PubMed DOI PMC

Baliakas P, Agathangelidis A, Hadzidimitriou A, Sutton L-A, Minga E, Tsanousa A, et al. . Not All IGHV3-21 Chronic Lymphocytic Leukemias Are Equal: Prognostic Considerations. Blood (2015) 125(5):856–9. 10.1182/blood-2014-09-600874 PubMed DOI PMC

Maity PC, Bilal M, Koning MT, Young M, van Bergen CAM, Renna V, et al. . IGLV3-21*01 is an Inherited Risk Factor for CLL Through the Acquisition of a Single-Point Mutation Enabling Autonomous BCR Signaling. Proc Natl Acad Sci U S A (2020) 117(8):4320–7. 10.1073/pnas.1913810117 PubMed DOI PMC

Nadeu F, Royo R, Clot G, Duran-Ferrer M, Navarro A, Martín S, et al. . IGLV3-21R110 Identifies an Aggressive Biological Subtype of Chronic Lymphocytic Leukemia With Intermediate Epigenetics. Blood (2021) 137(21):2935–46. 10.1182/blood.2020008311 PubMed DOI PMC

Cerhan JR, Slager SL. Familial Predisposition and Genetic Risk Factors for Lymphoma. Blood (2015) 126(20):2265–73. 10.1182/blood-2015-04-537498 PubMed DOI PMC

Goldin LR, Landgren O, Marti GE, Caporaso NE. Familial Aspects of Chronic Lymphocytic Leukemia, Monoclonal B-Cell Lymphocytosis (MBL), and Related Lymphomas. Eur J Clin Med Oncol (2010) 2(1):119–26. PubMed PMC

Goldin LR, Bjorkholm M, Kristinsson SY, Turesson I, Landgren O. Elevated Risk of Chronic Lymphocytic Leukemia and Other Indolent non-Hodgkin’s Lymphomas Among Relatives of Patients With Chronic Lymphocytic Leukemia. Haematologica (2009) 94(5):647–53. 10.3324/haematol.2008.003632 PubMed DOI PMC

Goldin LR, Lanasa MC, Slager SL, Cerhan JR, Vachon CM, Strom SS, et al. . Common Occurrence of Monoclonal B-Cell Lymphocytosis Among Members of High-Risk CLL Families. Br J Haematol (2010) 151(2):152–8. 10.1111/j.1365-2141.2010.08339.x PubMed DOI PMC

Di Bernardo MC, Crowther-Swanepoel D, Broderick P, Webb E, Sellick G, Wild R, et al. . A Genome-Wide Association Study Identifies Six Susceptibility Loci for Chronic Lymphocytic Leukemia. Nat Genet (2008) 40(10):1204–10. 10.1038/ng.219 PubMed DOI

Sellick GS, Goldin LR, Wild RW, Slager SL, Ressenti L, Strom SS, et al. . A High-Density SNP Genome-Wide Linkage Search of 206 Families Identifies Susceptibility Loci for Chronic Lymphocytic Leukemia. Blood (2007) 110(9):3326–33. 10.1182/blood-2007-05-091561 PubMed DOI PMC

Slager SL, Goldin LR, Strom SS, Lanasa MC, Spector LG, Rassenti L, et al. . Genetic Susceptibility Variants for Chronic Lymphocytic Leukemia. Cancer Epidemiol Biomarkers Prev (2010) 19(4):1098–102. 10.1158/1055-9965.EPI-09-1217 PubMed DOI PMC

Berndt SI, Skibola CF, Joseph V, Camp NJ, Nieters A, Wang Z, et al. . Genome-Wide Association Study Identifies Multiple Risk Loci for Chronic Lymphocytic Leukemia. Nat Genet (2013) 45(8):868–76. 10.1038/ng.2652 PubMed DOI PMC

Crowther-Swanepoel D, Broderick P, Di Bernardo MC, Dobbins SE, Torres M, Mansouri M, et al. . Common Variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 Influence Chronic Lymphocytic Leukemia Risk. Nat Genet (2010) 42(2):132–U159. 10.1038/ng.510 PubMed DOI PMC

Sava GP, Speedy HE, Di Bernardo MC, Dyer MJS, Holroyd A, Sunter NJ, et al. . Common Variation at 12q24.13 (OAS3) Influences Chronic Lymphocytic Leukemia Risk. Leukemia (2015) 29(3):748–51. 10.1038/leu.2014.311 PubMed DOI PMC

Slager SL, Rabe KG, Achenbach SJ, Vachon CM, Goldin LR, Strom SS, et al. . Genome-Wide Association Study Identifies a Novel Susceptibility Locus at 6p21.3 Among Familial CLL. Blood (2011) 117(6):1911–6. 10.1182/blood-2010-09-308205 PubMed DOI PMC

Speedy HE, Di Bernardo MC, Sava GP, Dyer MJS, Holroyd A, Wang Y, et al. . A Genome-Wide Association Study Identifies Multiple Susceptibility Loci for Chronic Lymphocytic Leukemia. Nat Genet (2014) 46(1):56–+. 10.1038/ng.2843 PubMed DOI

Langerak AW, Davi F, Ghia P, Hadzidimitriou A, Murray F, Potter KN, et al. . Immunoglobulin Sequence Analysis and Prognostication in CLL: Guidelines From the ERIC Review Board for Reliable Interpretation of Problematic Cases. Leukemia (2011) 25(6):979–84. 10.1038/leu.2011.49 PubMed DOI

van Dongen JJ, Langerak AW, Bruggemann M, Evans PAS, Hummel M, Lavender FL, et al. . Design and Standardization of PCR Primers and Protocols for Detection of Clonal Immunoglobulin and T-Cell Receptor Gene Recombinations in Suspect Lymphoproliferations: Report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia (2003) 17(12):2257–317. 10.1038/sj.leu.2403202 PubMed DOI

Bystry V, Reigl T, Krejci A, Demko M, Hanakova B, Grioni A, et al. . ARResT/Interrogate: An Interactive Immunoprofiler for IG/TR NGS Data. Bioinformatics (2017) 33(3):435–7. 10.1093/bioinformatics/btw634 PubMed DOI

van der Velden VHJ, Bruggemann M, Cazzaniga G, Scheijen B, Tops B, Trka J, et al. . Potential and Pitfalls of Whole Transcriptome-Based Immunogenetic Marker Identification in Acute Lymphoblastic Leukemia; a EuroMRD and EuroClonality-NGS Working Group Study. Leukemia (2021) 35(3):924–8. 10.1038/s41375-021-01154-z PubMed DOI PMC

Mayakonda A, Lin DC, Assenov Y, Plass C, Koeffler HP. Maftools: Efficient and Comprehensive Analysis of Somatic Variants in Cancer. Genome Res (2018) 28(11):1747–56. 10.1101/gr.239244.118 PubMed DOI PMC

Tate JG, Bamford S, Jubb HC, Sondka Z, Beare DM, Bindal N, et al. . COSMIC: The Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res (2019) 47(D1):D941–7. 10.1093/nar/gky1015 PubMed DOI PMC

Fernhout F, Dinkelaar RB, Hagemeijer A, Groeneveld K, van Kammen E, van Dongen JJ. Four Aged Siblings With B Cell Chronic Lymphocytic Leukemia. Leukemia (1997) 11(12):2060–5. 10.1038/sj.leu.2400874 PubMed DOI

Kriangkum J, Motz SN, Mack T, Beiggi S, Baigorri E, Kuppusamy H, et al. . Single-Cell Analysis and Next-Generation Immuno-Sequencing Show That Multiple Clones Persist in Patients With Chronic Lymphocytic Leukemia. PloS One (2015) 10(9):e0137232. 10.1371/journal.pone.0137232 PubMed DOI PMC

Hengeveld PJ, Levin MD, Kolijn PM, Langerak AW. Reading the B-Cell Receptor Immunome in Chronic Lymphocytic Leukemia: Revelations and Applications. Exp Hematol (2021) 93:14–24. 10.1016/j.exphem.2020.09.194 PubMed DOI

Raponi S, Ilari C, Della Starza I, Cappelli LV, Cafforio L, Piciocchi A, et al. . Redefining the Prognostic Likelihood of Chronic Lymphocytic Leukaemia Patients With Borderline Percentage of Immunoglobulin Variable Heavy Chain Region Mutations. Br J Haematol (2020) 189(5):853–9. 10.1111/bjh.16434 PubMed DOI

Gemenetzi K, Psomopoulos F, Carriles AA, Gounari M, Minici C, Plevova K, et al. . Higher-Order Immunoglobulin Repertoire Restrictions in CLL: The Illustrative Case of Stereotyped Subsets 2 and 169. Blood (2021) 137(14):1895–904. 10.1182/blood.2020005216 PubMed DOI

Marincevic M, Cahill N, Gunnarsson R, Isaksson A, Mansouri M, Göransson H, et al. . High-Density Screening Reveals a Different Spectrum of Genomic Aberrations in Chronic Lymphocytic Leukemia Patients With ‘Stereotyped’ IGHV3-21 and IGHV4-34 B-Cell Receptors. Haematologica (2010) 95(9):1519–25. 10.3324/haematol.2009.021014 PubMed DOI PMC

Fraschilla I, Jeffrey KL. The Speckled Protein (SP) Family: Immunity’s Chromatin Readers. Trends Immunol (2020) 41(7):572–85. 10.1016/j.it.2020.04.007 PubMed DOI PMC

Leeksma AC, Baliakas P, Moysiadis T, Puiggros A, Plevova K, Van der Kevie-Kersemaekers A-M, et al. . Genomic Arrays Identify High-Risk Chronic Lymphocytic Leukemia With Genomic Complexity: A Multi-Center Study. Haematologica (2021) 106(1):87–97. 10.3324/haematol.2019.239947 PubMed DOI PMC

Rack KA, van den Berg E, Haferlach C, Beverloo HB, Costa D, Espinet B, et al. . European Recommendations and Quality Assurance for Cytogenomic Analysis of Haematological Neoplasms: Reponse to the Comments From the Francophone Group of Hematological Cytogenetics (GFCH). Leukemia (2020) 34(8):2262–4. 10.1038/s41375-020-0736-x PubMed DOI PMC

Schoumans J, Suela J, Hastings R, Muehlematter D, Rack K, van den Berg E, et al. . Guidelines for Genomic Array Analysis in Acquired Haematological Neoplastic Disorders. Genes Chromosomes Cancer (2016) 55(5):480–91. 10.1002/gcc.22350 PubMed DOI

Kleiblova P, Stolarova L, Krizova K, Lhota F, Hojny J, Zemankova P, et al. . Identification of Deleterious Germline CHEK2 Mutations and Their Association With Breast and Ovarian Cancer. Int J Cancer (2019) 145(7):1782–97. 10.1002/ijc.32385 PubMed DOI

Rudd MF, Sellick GS, Webb EL, Catovsky D, Houlston RS. Variants in the ATM-BRCA2-CHEK2 Axis Predispose to Chronic Lymphocytic Leukemia. Blood (2006) 108(2):638–44. 10.1182/blood-2005-12-5022 PubMed DOI

Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. . Whole Genomes Redefine the Mutational Landscape of Pancreatic Cancer. Nature (2015) 518(7540):495–501. 10.1038/nature14169 PubMed DOI PMC

Yang X, Fu YJ, Hu FQ, Luo XL, Hu JB, Wang GH. PIK3R3 Regulates PPAR Alpha Expression to Stimulate Fatty Acid Beta-Oxidation and Decrease Hepatosteatosis. Exp Mol Med (2018) 50:e431–e431. 10.1038/emm.2017.243 PubMed DOI PMC

Moore NS, Aldubayan SH, Taylor-Weiner A, Stilgenbauer S, Getz G, Wu CJ, et al. . Inherited DNA Repair and Cell Cycle Gene Defects in Chronic Lymphocytic Leukemia. J Clin Oncol (2019) 37(15):1508–1508. 10.1200/JCO.2019.37.15_suppl.1508 DOI

Derenzini E, Mazzara S, Melle F, Motta G, Fabbri M, Bruna R, et al. . A 3-Gene Signature Based on MYC, BCL-2 and NFKBIA Improves Risk Stratification in Diffuse Large B-Cell Lymphoma. Haematologica (2020). 10.3324/haematol.2019.236455 PubMed DOI PMC

Wu B, Slabicki M, Sellner L, Dietrich S, Liu X, Jethwa A, et al. . MED12 Mutations and NOTCH Signalling in Chronic Lymphocytic Leukaemia. Br J Haematol (2017) 179(3):421–9. 10.1111/bjh.14869 PubMed DOI

Improgo MR, Tesar B, Klitgaard JL, Magori-Cohen R, Yu L, Kasar S, et al. . MYD88 L265P Mutations Identify a Prognostic Gene Expression Signature and a Pathway for Targeted Inhibition in CLL. Br J Haematol (2019) 184(6):925–36. 10.1111/bjh.15714 PubMed DOI

Herling CD, Klaumunzer M, Rocha CK, Altmüller J, Thiele H, Bahlo J, et al. . Complex Karyotypes and KRAS and POT1 Mutations Impact Outcome in CLL After Chlorambucil-Based Chemotherapy or Chemoimmunotherapy. Blood (2016) 128(3):395–404. 10.1182/blood-2016-01-691550 PubMed DOI

Vendramini E, Bomben R, Pozzo F, Benedetti D, Bittolo T, Rossi FM, et al. . KRAS, NRAS, and BRAF Mutations Are Highly Enriched in Trisomy 12 Chronic Lymphocytic Leukemia and Are Associated With Shorter Treatment-Free Survival. Leukemia (2019) 33(8):2111–5. 10.1038/s41375-019-0444-6 PubMed DOI PMC

Hoofd C, Huang SJ, Gusscott S, Lam S, Wong R, Johnston A, et al. . Ultrasensitive Detection of NOTCH1 C.7544_7545delct Mutations in Chronic Lymphocytic Leukemia by Droplet Digital PCR Reveals High Frequency of Subclonal Mutations and Predicts Clinical Outcome in Cases With Trisomy 12. J Mol Diagn (2020) 22(4):571–8. 10.1016/j.jmoldx.2020.01.008 PubMed DOI

Kasar S, Kim J, Improgo R, Tiao G, Polak P, Haradhvala N, et al. . Whole-Genome Sequencing Reveals Activation-Induced Cytidine Deaminase Signatures During Indolent Chronic Lymphocytic Leukaemia Evolution. Nat Commun (2015) 6:1–12. 10.1038/ncomms9866 PubMed DOI PMC

Klein U, Dalla-Favera R. New Insights Into the Pathogenesis of Chronic Lymphocytic Leukemia. Semin Cancer Biol (2010) 20(6):377–83. 10.1016/j.semcancer.2010.10.012 PubMed DOI

Ghia EM, Jain S, Widhopf GF, Rassenti LZ, Keating MJ, Wierda WG, et al. . Use of IGHV3-21 in Chronic Lymphocytic Leukemia Is Associated With High-Risk Disease and Reflects Antigen-Driven, Post-Germinal Center Leukemogenic Selection. Blood (2008) 111(10):5101–8. 10.1182/blood-2007-12-130229 PubMed DOI PMC

Ecker V, Stumpf M, Brandmeier L, Neumayer T, Pfeuffer L, Engleitner T, et al. . Targeted PI3K/AKT-Hyperactivation Induces Cell Death in Chronic Lymphocytic Leukemia. Nat Commun (2021) 12(1):3526. 10.1038/s41467-021-23752-2 PubMed DOI PMC

Goldin LR, Slager SL. Familial CLL: Genes and Environment. Hematol Am Soc Hematol Educ Program (2007) 1:339–45. 10.1182/asheducation-2007.1.339 PubMed DOI