{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T15:46:48Z","timestamp":1772034408271,"version":"3.50.1"},"reference-count":76,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T00:00:00Z","timestamp":1618185600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Chronic lymphocytic leukemia (CLL)\/Small lymphocytic lymphoma (SLL) is a heterogeneous disease consisting of at least two separate subtypes, based on the mutation status of the immunoglobulin heavy chain variable gene (IGHV) sequence. Exposure to antigens seems to play a role in malignant transformation and in the selection and expansion of more aggressive CLL clones. Furthermore, a biased usage of particular IGHV gene subgroups and the existence of stereotyped B-cell receptors (BCRs) are distinctive characteristics of human CLL. We have previously described that<jats:italic>Traf2<\/jats:italic>DN\/<jats:italic>BCL2<\/jats:italic>double-transgenic (tg,<jats:sup>+\/+<\/jats:sup>) mice develop CLL\/SLL with high incidence with aging. In this model, TNF-Receptor Associated Factor (TRAF)-2 deficiency cooperates with B cell lymphoma (BCL)-2 in promoting CLL\/SLL in mice by specifically enforcing marginal zone (MZ) B cell differentiation and rendering B cells independent of BAFF for survival. In this report, we have performed the sequencing of the IGHV-D-J rearrangements of B cell clones from the<jats:italic>Traf2<\/jats:italic>DN\/<jats:italic>BCL2<\/jats:italic>-tg<jats:sup>+\/+<\/jats:sup>mice with CLL\/SLL. The results indicate that these mice develop oligoclonal and monoclonal B cell expansions. Allotransplantation of the oligoclonal populations into immunodeficient mice resulted in the preferential expansion of one of the parental clones. The analysis of the IGHV sequences indicated that 15% were mutated (M) and 85% unmutated (UM). Furthermore, while the<jats:italic>Traf2<\/jats:italic>DN\/<jats:italic>BCL2<\/jats:italic>-tg<jats:sup>-\/-<\/jats:sup>(wild-type),<jats:sup>-\/+<\/jats:sup>(<jats:italic>BCL2<\/jats:italic>single-tg) and<jats:sup>+\/-<\/jats:sup>(<jats:italic>Traf2DN<\/jats:italic>DN single-tg) littermates showed the expression of various IGHV gene subgroups, the CLL\/SLL expanded clones from the<jats:italic>Traf2<\/jats:italic>DN\/<jats:italic>BCL2<\/jats:italic>-tg<jats:sup>+\/+<\/jats:sup>(double-transgenic) mice showed a more restricted IGHV gene subgroup usage and an overrepresentation of particular IGHV genes. In addition, the HCDR3-encoded protein sequence indicates the existence of stereotyped immunoglobulin (Ig) in the BCRs and strong similarities with BCR recognizing autoantigens and pathogen-associated antigens. Altogether, these results highlight the remarkable similarities between the CLL\/SLL developed by the<jats:italic>Traf2<\/jats:italic>DN\/<jats:italic>BCL2<\/jats:italic>-tg<jats:sup>+\/+<\/jats:sup>mice and its human counterpart.<\/jats:p>","DOI":"10.3389\/fimmu.2021.627602","type":"journal-article","created":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T05:55:26Z","timestamp":1618206926000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The Traf2DNxBCL2-tg Mouse Model of Chronic Lymphocytic Leukemia\/Small Lymphocytic Lymphoma Recapitulates the Biased IGHV Gene Usage, Stereotypy, and Antigen-Specific HCDR3 Selection of Its Human Counterpart"],"prefix":"10.3389","volume":"12","author":[{"given":"Gema","family":"Perez-Chacon","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan M.","family":"Zapata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra041720","article-title":"Chronic lymphocytic leukemia","volume":"352","author":"Chiorazzi","year":"2005","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-07-155663","article-title":"Cellular origin(s) of chronic lymphocytic leukemia: cautionary notes and additional considerations and possibilities","volume":"117","author":"Chiorazzi","year":"2011","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","first-page":"16096","DOI":"10.1038\/nrdp.2016.96","article-title":"Chronic lymphocytic leukaemia","volume":"3","author":"Kipps","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/0167-5699(94)90009-4","article-title":"The pathogenesis of chronic lymphocytic leukemia: analysis of the antibody repertoire","volume":"15","author":"Schroeder","year":"1994","journal-title":"Immunol Today"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1172\/JCI3009","article-title":"Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors","volume":"102","author":"Fais","year":"1998","journal-title":"J Clin Invest"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V94.6.1848.418k05_1848_1854","article-title":"Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia","volume":"94","author":"Hamblin","year":"1999","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V94.6.1840","article-title":"Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia","volume":"94","author":"Damle","year":"1999","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.1.377.013k56f_377_379","article-title":"Expression of unmutated VH genes is a detrimental prognostic factor in chronic lymphocytic leukemia","volume":"96","author":"Maloum","year":"2000","journal-title":"Blood"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V99.11.4087","article-title":"B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes","volume":"99","author":"Damle","year":"2002","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1084\/jem.194.11.1625","article-title":"Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells","volume":"194","author":"Klein","year":"2001","journal-title":"J Exp Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1038\/leu.2017.311","article-title":"Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHV(mut) and IgHV(unmut) subgroups","volume":"32","author":"Burns","year":"2018","journal-title":"Leukemia"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24387","article-title":"Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity","volume":"115","author":"Herve","year":"2005","journal-title":"J Clin Invest"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-03-1563","article-title":"B-cell receptor translocation to lipid rafts and associated signaling differ between prognostically important subgroups of chronic lymphocytic leukemia","volume":"65","author":"Allsup","year":"2005","journal-title":"Cancer Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2009.186","article-title":"A different ontogenesis for chronic lymphocytic leukemia cases carrying stereotyped antigen receptors: molecular and computational evidence","volume":"24","author":"Darzentas","year":"2010","journal-title":"Leukemia"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020007039","article-title":"Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL","volume":"137","author":"Agathangelidis","year":"2020","journal-title":"Blood"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1196\/annals.1358.002","article-title":"B-cell chronic lymphocytic leukemia, a clonal disease of B lymphocytes with receptors that vary in specificity for (auto)antigens","volume":"1062","author":"Chiorazzi","year":"2005","journal-title":"Ann N Y Acad Sci"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2796.2008.02030.x","article-title":"Microenvironmental influences in chronic lymphocytic leukaemia: the role of antigen stimulation","volume":"264","author":"Ghia","year":"2008","journal-title":"J Intern Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2012.268","article-title":"Xenograft models of chronic lymphocytic leukemia: problems, pitfalls and future directions","volume":"27","author":"Bertilaccio","year":"2013","journal-title":"Leukemia"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-12-324210","article-title":"A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease","volume":"117","author":"Bagnara","year":"2011","journal-title":"Blood"},{"key":"B20","doi-asserted-by":"crossref","DOI":"10.5772\/27091","article-title":"Mouse Models of Chronic Lymphocytic Leukemia","volume-title":"Chronic Lymphocytic Leukemia","author":"Perez-Chacon","year":"2012"},{"key":"B21","doi-asserted-by":"publisher","first-page":"e2071","DOI":"10.1038\/cddis.2015.419","article-title":"TCL1 transgenic mouse model as a tool for the study of therapeutic targets and microenvironment in human B-cell chronic lymphocytic leukemia","volume":"7","author":"Bresin","year":"2016","journal-title":"Cell Death Dis"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407541101","article-title":"TNF receptor-associated factor (TRAF) domain and Bcl-2 cooperate to induce small B cell lymphoma\/chronic lymphocytic leukemia in transgenic mice","volume":"101","author":"Zapata","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e559","DOI":"10.1371\/journal.pone.0000559","article-title":"Triterpenoids display single agent anti-tumor activity in a transgenic mouse model of chronic lymphocytic leukemia and small lymphocytic lymphoma","volume":"2","author":"Kress","year":"2007","journal-title":"PLoS One"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200814","article-title":"TNFR-associated factor 2 deficiency in B lymphocytes predisposes to chronic lymphocytic leukemia\/small lymphocytic lymphoma in mice","volume":"189","author":"Perez-Chacon","year":"2012","journal-title":"J Immunol"},{"key":"B25","article-title":"Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome","volume":"10","author":"Robertson","year":"1996","journal-title":"Leukemia"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80390-8","article-title":"TRAF2 is essential for JNK but not NF-KB activation and regulates lymphocyte proliferation and survival","volume":"7","author":"Lee","year":"1997","journal-title":"Immunity"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.23.11376","article-title":"Differential effects of Bcl-2 on B and T lymphocytes in transgenic mice","volume":"89","author":"Katsumata","year":"1992","journal-title":"Proc Natl Acad Sci USA"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0604564103","article-title":"B cell receptors in TCL1 transgenic mice resemble those of aggressive, treatment-resistant human chronic lymphocytic leukemia","volume":"103","author":"Yan","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn316","article-title":"IMGT\/V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis","volume":"36","author":"Brochet","year":"2008","journal-title":"Nucleic Acids Res"},{"key":"B30","doi-asserted-by":"crossref","first-page":"49","DOI":"10.5772\/intechopen.69110","article-title":"Somatic Hypermutational Status and Gene Repertoire of Immunoglobulin Rearrangements in Chronic Lymphocytic Leukemia","volume-title":"Lymphocyte Updates - Cancer, Autoimmunity and Infection","author":"Karan-Djurasevic","year":"2017"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-07-587790","article-title":"Two types of BCR interactions are positively selected during leukemia development in the Emu-TCL1 transgenic mouse model of CLL","volume":"125","author":"Iacovelli","year":"2015","journal-title":"Blood"},{"key":"B32","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.ccr.2009.11.019","article-title":"The DLEU2\/miR-15a\/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia","volume":"17","author":"Klein","year":"2010","journal-title":"Cancer Cell"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2014.0236","article-title":"The mouse antibody heavy chain repertoire is germline-focused and highly variable between inbred strains. Philosophical transactions of the Royal Society of London Series B","volume":"370","author":"Collins","year":"2015","journal-title":"Biol Sci"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.03114","article-title":"Dysregulated TRAF3 and BCL2 Expression Promotes Multiple Classes of Mature Non-hodgkin B Cell Lymphoma in Mice","volume":"9","author":"Perez-Chacon","year":"2019","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"e0190982","DOI":"10.1371\/journal.pone.0190982","article-title":"Characterization of the naive murine antibody repertoire using unamplified high-throughput sequencing","volume":"13","author":"Rettig","year":"2018","journal-title":"PLoS One"},{"key":"B36","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1111\/imcb.12288","article-title":"A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild-derived and classical inbred mouse strains","volume":"97","author":"Watson","year":"2019","journal-title":"Immunol Cell Biol"},{"key":"B37","article-title":"Patients with chronic lymphocytic leukemia with mutated VH genes presenting with Binet stage B or C form a subgroup with a poor outcome","volume":"90","author":"Tobin","year":"2005","journal-title":"Haematologica"},{"key":"B38","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/j.immuni.2008.01.009","article-title":"TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor","volume":"28","author":"Gardam","year":"2008","journal-title":"Immunity"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/nri799","article-title":"Marginal-zone B cells","volume":"2","author":"Martin","year":"2002","journal-title":"Nat Rev Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.2006.001758.x","article-title":"Somatic hypermutation of Ig genes is affected differently by failures in apoptosis caused by disruption of Fas (lpr mutation) or by overexpression of Bcl-2","volume":"63","author":"Mastache","year":"2006","journal-title":"Scandinavian J Immunol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1111\/j.1365-2141.2005.05480.x","article-title":"Immunoglobulin gene segment usage, location and immunogenicity in mutated and unmutated chronic lymphocytic leukaemia","volume":"129","author":"Mauerer","year":"2005","journal-title":"Br J Haematol"},{"key":"B42","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.158.1.235","article-title":"Ig VH1 genes expressed in B cell chronic lymphocytic leukemia exhibit distinctive molecular features","volume":"158","author":"Johnson","year":"1997","journal-title":"J Immunol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"95","DOI":"10.4049\/jimmunol.166.1.95","article-title":"Normal B cells express 51p1-encoded Ig heavy chains that are distinct from those expressed by chronic lymphocytic leukemia B cells","volume":"166","author":"Widhopf","year":"2001","journal-title":"J Immunol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/1742-4682-11-30","article-title":"Comparative analysis of human and mouse immunoglobulin variable heavy regions from IMGT\/LIGM-DB with IMGT\/HighV-QUEST","volume":"11","author":"Shi","year":"2014","journal-title":"Theor Biol Med Model"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01996","article-title":"Identification of Distinct Unmutated Chronic Lymphocytic Leukemia Subsets in Mice Based on Their T Cell Dependency","volume":"9","author":"Pal Singh","year":"2018","journal-title":"Front Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-11-393694","article-title":"Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies","volume":"119","author":"Agathangelidis","year":"2012","journal-title":"Blood"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2013.879715","article-title":"Stereotyped B-cell receptors in chronic lymphocytic leukemia","volume":"55","author":"Agathangelidis","year":"2014","journal-title":"Leuk Lymphoma"},{"key":"B48","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s10020-020-00151-9","article-title":"Tracing CLL-biased stereotyped immunoglobulin gene rearrangements in normal B cell subsets using a high-throughput immunogenetic approach","volume":"26","author":"Colombo","year":"2020","journal-title":"Mol Med"},{"key":"B49","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/s12979-019-0163-x","article-title":"The presence of CLL-associated stereotypic B cell receptors in the normal BCR repertoire from healthy individuals increases with age","volume":"16","author":"Muggen","year":"2019","journal-title":"Immun Ageing"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-08-447904","article-title":"Autoantigenic targets of B-cell receptors derived from chronic lymphocytic leukemias bind to and induce proliferation of leukemic cells","volume":"121","author":"Zwick","year":"2013","journal-title":"Blood"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1300616110","article-title":"Autoantigen can promote progression to a more aggressive TCL1 leukemia by selecting variants with enhanced B-cell receptor signaling","volume":"110","author":"Chen","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20160712","article-title":"Early generated B1 B cells with restricted BCRs become chronic lymphocytic leukemia with continued c-Myc and low Bmf expression","volume":"213","author":"Hayakawa","year":"2016","journal-title":"J Exp Med"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2016.61","article-title":"Loss of a chromosomal region with synteny to human 13q14 occurs in mouse chronic lymphocytic leukemia that originates from early-generated B-1 B cells","volume":"30","author":"Hayakawa","year":"2016","journal-title":"Leukemia"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201707732","article-title":"Pathogen-specific B-cell receptors drive chronic lymphocytic leukemia by light-chain-dependent cross-reaction with autoantigens","volume":"9","author":"Jimenez de Oya","year":"2017","journal-title":"EMBO Mol Med"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/0896-8411(88)90068-6","article-title":"Chronic lymphocytic leukemic (CLL) cells secrete multispecific autoantibodies","volume":"1","author":"Broker","year":"1988","journal-title":"J Autoimmun"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-11-125450","article-title":"A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies","volume":"111","author":"Lanemo Myhrinder","year":"2008","journal-title":"Blood"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1084\/jem.169.1.255","article-title":"Production of autoantibodies by CD5-expressing B lymphocytes from patients with chronic lymphocytic leukemia","volume":"169","author":"Sthoeger","year":"1989","journal-title":"J Exp Med"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2008.379","article-title":"Molecular evidence for EBV and CMV persistence in a subset of patients with chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors","volume":"23","author":"Kostareli","year":"2009","journal-title":"Leukemia"},{"key":"B59","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1111\/j.1365-2362.2009.02131.x","article-title":"Relative seroprevalence of human herpes viruses in patients with chronic lymphocytic leukaemia","volume":"39","author":"Steininger","year":"2009","journal-title":"Eur J Clin Invest"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.21.120601.141018","article-title":"B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor","volume":"21","author":"Chiorazzi","year":"2003","journal-title":"Annu Rev Immunol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0303-x","article-title":"The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia","volume":"33","author":"Ten Hacken","year":"2019","journal-title":"Leukemia"},{"key":"B62","article-title":"Analysis of VH genes in marginal zone lymphoma reveals marked heterogeneity between splenic and nodal tumors and suggests the existence of clonal selection","volume":"90","author":"Traverse-Glehen","year":"2005","journal-title":"Haematologica"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-019-02712-8","article-title":"IGHV mutational status of nodal marginal zone lymphoma by NGS reveals distinct pathogenic pathways with different prognostic implications","volume":"477","author":"Granai","year":"2020","journal-title":"Virchows Arch"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2009.01341.x","article-title":"Immunoglobulin heavy chain variable region gene usage and mutational status of the leukemic B cells in Iranian patients with chronic lymphocytic leukemia","volume":"100","author":"Hojjat-Farsangi","year":"2009","journal-title":"Cancer Sci"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7819","article-title":"Immunoglobulin gene rearrangements in Chinese and Italian patients with chronic lymphocytic leukemia","volume":"7","author":"Marinelli","year":"2016","journal-title":"Oncotarget"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/S0145-305X(03)00078-8","article-title":"IMGT\/PhyloGene: an on-line tool for comparative analysis of immunoglobulin and T cell receptor genes","volume":"27","author":"Elemento","year":"2003","journal-title":"Dev Comp Immunol"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20120833","article-title":"Cellular origin and pathophysiology of chronic lymphocytic leukemia","volume":"209","author":"Seifert","year":"2012","journal-title":"J Exp Med"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00683","article-title":"Chronic Lymphocytic Leukemia B-Cell Normal Cellular Counterpart: Clues From a Functional Perspective","volume":"9","author":"Darwiche","year":"2018","journal-title":"Front Immunol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/nri3383","article-title":"Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes","volume":"13","author":"Cerutti","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1615\/CritRevImmunol.2018024985","article-title":"Heterogeneity of Memory Marginal Zone B Cells","volume":"38","author":"Hendricks","year":"2018","journal-title":"Crit Rev Immunol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2004.09.011","article-title":"TRAF2 differentially regulates the canonical and noncanonical pathways of NF-kappaB activation in mature B cells","volume":"21","author":"Grech","year":"2004","journal-title":"Immunity"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28281","article-title":"Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737","volume":"117","author":"Del Gaizo Moore","year":"2007","journal-title":"J Clin Invest"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.021908.132607","article-title":"Human marginal zone B cells","volume":"27","author":"Weill","year":"2009","journal-title":"Annu Rev Immunol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.102181599","article-title":"Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression","volume":"99","author":"Bichi","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700568","article-title":"Massively Parallel Sequencing of Peritoneal and Splenic B Cell Repertoires Highlights Unique Properties of B-1 Cell Antibodies","volume":"200","author":"Prohaska","year":"2018","journal-title":"J Immunol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1038\/nature11309","article-title":"Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling","volume":"489","author":"Duhren-von Minden","year":"2012","journal-title":"Nature"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.627602\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T23:33:18Z","timestamp":1698881598000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.627602\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,12]]},"references-count":76,"alternative-id":["10.3389\/fimmu.2021.627602"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.627602","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,12]]},"article-number":"627602"}}