{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:00:31Z","timestamp":1790805631317,"version":"4.1.0"},"reference-count":61,"publisher":"American Society of Hematology","issue":"12","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,9,23]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>B-cell receptor (BCR) signals play a critical role in the pathogenesis of chronic lymphocytic leukemia (CLL), but their role in regulating CLL cell proliferation has still not been firmly established. Unlike normal B cells, CLL cells do not proliferate in vitro upon engagement of the BCR, suggesting that CLL cell proliferation is regulated by other signals from the microenvironment, such as those provided by Toll-like receptors or T cells. Here, we report that BCR engagement of human and murine CLL cells induces several positive regulators of the cell cycle, but simultaneously induces the negative regulators CDKN1A, CDKN2A, and CDKN2B, which block cell-cycle progression. We further show that introduction of genetic lesions that downregulate these cell-cycle inhibitors, such as inactivating lesions in CDKN2A, CDKN2B, and the CDKN1A regulator TP53, leads to more aggressive disease in a murine in vivo CLL model and spontaneous proliferation in vitro that is BCR dependent but independent of costimulatory signals. Importantly, inactivating lesions in CDKN2A, CDKN2B, and TP53 frequently co-occur in Richter syndrome (RS), and BCR stimulation of human RS cells with such lesions is sufficient to induce proliferation. We also show that tumor cells with combined TP53 and CDKN2A\/2B abnormalities remain sensitive to BCR-inhibitor treatment and are synergistically sensitive to the combination of a BCR and cyclin-dependent kinase 4 and 6 (CDK4\/6) inhibitor both in vitro and in vivo. These data provide evidence that BCR signals are directly involved in driving CLL cell proliferation and reveal a novel mechanism of Richter transformation.<\/jats:p>","DOI":"10.1182\/blood.2020008276","type":"journal-article","created":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T13:09:03Z","timestamp":1619442543000},"page":"1053-1066","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":63,"title":["B-cell receptor signaling and genetic lesions in TP53 and CDKN2A\/CDKN2B cooperate in Richter transformation"],"prefix":"10.1182","volume":"138","author":[{"given":"Supriya","family":"Chakraborty","sequence":"first","affiliation":[{"name":"Molecular Hematology Unit, International Center for Genetic Engineering and Biotechnology, Trieste, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7136-7174","authenticated-orcid":false,"given":"Claudio","family":"Martines","sequence":"additional","affiliation":[{"name":"Molecular Hematology Unit, International Center for Genetic Engineering and Biotechnology, Trieste, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6612-3068","authenticated-orcid":false,"given":"Fabiola","family":"Porro","sequence":"additional","affiliation":[{"name":"Molecular Hematology Unit, International Center for Genetic Engineering and Biotechnology, Trieste, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Fortunati","sequence":"additional","affiliation":[{"name":"Molecular Hematology Unit, International Center for Genetic Engineering and Biotechnology, Trieste, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3634-6527","authenticated-orcid":false,"given":"Alice","family":"Bonato","sequence":"additional","affiliation":[{"name":"Molecular Hematology Unit, International Center for Genetic Engineering and Biotechnology, Trieste, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marija","family":"Dimishkovska","sequence":"additional","affiliation":[{"name":"Research Center for Genetic Engineering and Biotechnology, Macedonian Academy of Sciences and Arts, Skopje, North Macedonia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7156-5434","authenticated-orcid":false,"given":"Silvano","family":"Piazza","sequence":"additional","affiliation":[{"name":"Computational Biology Unit, International Center for Genetic Engineering and Biotechnology, Trieste, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3095-3369","authenticated-orcid":false,"given":"Brijesh S.","family":"Yadav","sequence":"additional","affiliation":[{"name":"University of Information Science & Technology St Paul the Apostle, Ohrid, North Macedonia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Idanna","family":"Innocenti","sequence":"additional","affiliation":[{"name":"Department of Hematology, Catholic University Hospital A. Gemelli, Rome, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Fazio","sequence":"additional","affiliation":[{"name":"Molecular Hematology Unit, International Center for Genetic Engineering and Biotechnology, Trieste, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Vaisitti","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, Turin, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0632-5036","authenticated-orcid":false,"given":"Silvia","family":"Deaglio","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, University of Turin, Turin, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6203-7966","authenticated-orcid":false,"given":"Alberto","family":"Zam\u00f2","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University of W\u00fcrzburg, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandar J.","family":"Dimovski","sequence":"additional","affiliation":[{"name":"Research Center for Genetic Engineering and Biotechnology, Macedonian Academy of Sciences and Arts, Skopje, North Macedonia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8327-1396","authenticated-orcid":false,"given":"Luca","family":"Laurenti","sequence":"additional","affiliation":[{"name":"Department of Hematology, Catholic University Hospital A. Gemelli, Rome, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9081-5462","authenticated-orcid":false,"given":"Dimitar G.","family":"Efremov","sequence":"additional","affiliation":[{"name":"Molecular Hematology Unit, International Center for Genetic Engineering and Biotechnology, Trieste, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2021,4,28]]},"reference":[{"key":"2021092315292420400_B1","doi-asserted-by":"crossref","first-page":"16096","DOI":"10.1038\/nrdp.2016.96","article-title":"Chronic lymphocytic leukaemia [published correction appears in Nat Rev Dis Primers. 2017;3:17008]","volume":"3","author":"Kipps","year":"2017","journal-title":"Nat Rev Dis Primers."},{"issue":"11","key":"2021092315292420400_B2","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/s41571-019-0239-8","article-title":"Chronic lymphocytic leukaemia: from genetics to treatment","volume":"16","author":"Bosch","year":"2019","journal-title":"Nat Rev Clin Oncol."},{"issue":"2","key":"2021092315292420400_B3","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/cr.2012.152","article-title":"Chronic lymphocytic leukemia: a tale of one or two signals?","volume":"23","author":"Chiorazzi","year":"2013","journal-title":"Cell Res."},{"issue":"4","key":"2021092315292420400_B4","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1084\/jem.20040544","article-title":"Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia","volume":"200","author":"Messmer","year":"2004","journal-title":"J Exp Med."},{"issue":"19","key":"2021092315292420400_B5","doi-asserted-by":"crossref","first-page":"4467","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."},{"issue":"6","key":"2021092315292420400_B6","doi-asserted-by":"crossref","first-page":"1840","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."},{"issue":"6","key":"2021092315292420400_B7","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1182\/blood.V94.6.1848","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."},{"issue":"2","key":"2021092315292420400_B8","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1182\/blood-2010-05-284984","article-title":"The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia","volume":"117","author":"Herishanu","year":"2011","journal-title":"Blood."},{"issue":"5","key":"2021092315292420400_B9","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1517\/13543784.2011.570329","article-title":"The Syk kinase as a therapeutic target in leukemia and lymphoma","volume":"20","author":"Efremov","year":"2011","journal-title":"Expert Opin Investig Drugs."},{"issue":"3","key":"2021092315292420400_B10","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/nrc.2017.121","article-title":"Targeting B cell receptor signalling in cancer: preclinical and clinical advances","volume":"18","author":"Burger","year":"2018","journal-title":"Nat Rev Cancer."},{"issue":"10","key":"2021092315292420400_B11","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1182\/blood-2014-07-587790","article-title":"Two types of BCR interactions are positively selected during leukemia development in the E\u03bc-TCL1 transgenic mouse model of CLL","volume":"125","author":"Iacovelli","year":"2015","journal-title":"Blood."},{"issue":"1","key":"2021092315292420400_B12","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1189\/jlb.72.1.83","article-title":"Modulation of malignant B cell activation and apoptosis by bcl-2 antisense ODN and immunostimulatory CpG ODN","volume":"72","author":"Jahrsd\u00f6rfer","year":"2002","journal-title":"J Leukoc Biol."},{"issue":"17","key":"2021092315292420400_B13","doi-asserted-by":"crossref","first-page":"3010","DOI":"10.1182\/blood-2012-11-467670","article-title":"IL-21 and CD40L signals from autologous T cells can induce antigen-independent proliferation of CLL cells","volume":"122","author":"Pascutti","year":"2013","journal-title":"Blood."},{"issue":"1","key":"2021092315292420400_B14","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41598-018-36853-8","article-title":"BCR-associated factors driving chronic lymphocytic leukemia cells proliferation ex vivo","volume":"9","author":"Schleiss","year":"2019","journal-title":"Sci Rep."},{"issue":"23","key":"2021092315292420400_B15","doi-asserted-by":"crossref","first-page":"4894","DOI":"10.1182\/blood-2010-03-275180","article-title":"The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the E\u03bc-TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling","volume":"116","author":"Suljagic","year":"2010","journal-title":"Blood."},{"issue":"8","key":"2021092315292420400_B16","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1038\/leu.2013.37","article-title":"Fostamatinib inhibits B-cell receptor signaling, cellular activation and tumor proliferation in patients with relapsed and refractory chronic lymphocytic leukemia","volume":"27","author":"Herman","year":"2013","journal-title":"Leukemia."},{"issue":"21","key":"2021092315292420400_B17","doi-asserted-by":"crossref","first-page":"3286","DOI":"10.1182\/blood-2014-02-548610","article-title":"Ibrutinib inhibits BCR and NF-\u03baB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL","volume":"123","author":"Herman","year":"2014","journal-title":"Blood."},{"issue":"4","key":"2021092315292420400_B18","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1038\/leu.2015.316","article-title":"BTK inhibition results in impaired CXCR4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia","volume":"30","author":"Chen","year":"2016","journal-title":"Leukemia."},{"issue":"19","key":"2021092315292420400_B19","doi-asserted-by":"crossref","first-page":"5814","DOI":"10.1158\/1078-0432.CCR-17-0650","article-title":"Combined BTK and PI3K\u03b4 inhibition with acalabrutinib and ACP-319 improves survival and tumor control in CLL mouse model","volume":"23","author":"Niemann","year":"2017","journal-title":"Clin Cancer Res."},{"issue":"2","key":"2021092315292420400_B20","doi-asserted-by":"crossref","first-page":"e89904","DOI":"10.1172\/jci.insight.89904","article-title":"Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib","volume":"2","author":"Burger","year":"2017","journal-title":"JCI Insight."},{"issue":"14","key":"2021092315292420400_B21","doi-asserted-by":"crossref","first-page":"7158","DOI":"10.1158\/0008-5472.CAN-06-0085","article-title":"Survival response to B-cell receptor ligation is restricted to progressive chronic lymphocytic leukemia cells irrespective of Zap70 expression","volume":"66","author":"Deglesne","year":"2006","journal-title":"Cancer Res."},{"issue":"3","key":"2021092315292420400_B22","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1182\/blood-2007-12-127688","article-title":"BCR ligation induced by IgM stimulation results in gene expression and functional changes only in IgV H unmutated chronic lymphocytic leukemia (CLL) cells","volume":"112","author":"Guarini","year":"2008","journal-title":"Blood."},{"issue":"1","key":"2021092315292420400_B23","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1182\/blood-2011-07-370403","article-title":"Surface IgM stimulation induces MEK1\/2-dependent MYC expression in chronic lymphocytic leukemia cells","volume":"119","author":"Krysov","year":"2012","journal-title":"Blood."},{"issue":"11","key":"2021092315292420400_B24","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1084\/jem.20131448","article-title":"Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome","volume":"210","author":"Fabbri","year":"2013","journal-title":"J Exp Med."},{"issue":"15","key":"2021092315292420400_B25","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1182\/blood-2013-03-489518","article-title":"Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome","volume":"122","author":"Chigrinova","year":"2013","journal-title":"Blood."},{"issue":"25","key":"2021092315292420400_B26","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1182\/blood-2018-01-791376","article-title":"Biology and treatment of Richter syndrome","volume":"131","author":"Rossi","year":"2018","journal-title":"Blood."},{"issue":"25","key":"2021092315292420400_B27","doi-asserted-by":"crossref","first-page":"3192","DOI":"10.1182\/blood-2015-10-675009","article-title":"BCR signaling inhibitors differ in their ability to overcome Mcl-1-mediated resistance of CLL B cells to ABT-199","volume":"127","author":"Bojarczuk","year":"2016","journal-title":"Blood."},{"issue":"9","key":"2021092315292420400_B28","doi-asserted-by":"crossref","first-page":"e59","DOI":"10.1093\/nar\/gkv126","article-title":"Fast and sensitive detection of indels induced by precise gene targeting","volume":"43","author":"Yang","year":"2015","journal-title":"Nucleic Acids Res."},{"issue":"1","key":"2021092315292420400_B29","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s12964-019-0327-5","article-title":"Therapeutic effect of palbociclib in chondrosarcoma: implication of cyclin-dependent kinase 4 as a potential target","volume":"17","author":"Ouyang","year":"2019","journal-title":"Cell Commun Signal."},{"issue":"23","key":"2021092315292420400_B30","doi-asserted-by":"crossref","first-page":"2890","DOI":"10.1182\/blood-2015-11-683581","article-title":"Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6","volume":"127","author":"Uras","year":"2016","journal-title":"Blood."},{"issue":"10","key":"2021092315292420400_B31","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1038\/s41375-019-0442-8","article-title":"Inhibition of SYK or BTK augments venetoclax sensitivity in SHP1-negative\/BCL-2-positive diffuse large B-cell lymphoma","volume":"33","author":"Sasi","year":"2019","journal-title":"Leukemia."},{"issue":"22","key":"2021092315292420400_B32","doi-asserted-by":"crossref","first-page":"19102","DOI":"10.18632\/oncotarget.3905","article-title":"The SIRT1\/TP53 axis is activated upon B-cell receptor triggering via miR-132 up-regulation in chronic lymphocytic leukemia cells","volume":"6","author":"Dal Bo","year":"2015","journal-title":"Oncotarget."},{"issue":"31","key":"2021092315292420400_B33","doi-asserted-by":"crossref","first-page":"11713","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."},{"issue":"16","key":"2021092315292420400_B34","doi-asserted-by":"crossref","first-page":"E1500","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."},{"issue":"5","key":"2021092315292420400_B35","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.3109\/10428194.2012.723706","article-title":"MGA, a suppressor of MYC, is recurrently inactivated in high risk chronic lymphocytic leukemia","volume":"54","author":"De Paoli","year":"2013","journal-title":"Leuk Lymphoma."},{"issue":"5","key":"2021092315292420400_B36","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.3324\/haematol.2019.217307","article-title":"Genomic alterations in high-risk chronic lymphocytic leukemia frequently affect cell cycle key regulators and NOTCH1-regulated transcription","volume":"105","author":"Edelmann","year":"2020","journal-title":"Haematologica."},{"issue":"13","key":"2021092315292420400_B37","doi-asserted-by":"crossref","first-page":"3413","DOI":"10.1158\/0008-5472.CAN-17-4004","article-title":"Novel Richter syndrome xenograft models to study genetic architecture, biology, and therapy responses","volume":"78","author":"Vaisitti","year":"2018","journal-title":"Cancer Res."},{"issue":"1","key":"2021092315292420400_B38","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1385\/IR:27:1:31","article-title":"Cell cycle control mechanisms in B-1 and B-2 lymphoid subsets","volume":"27","author":"Piatelli","year":"2003","journal-title":"Immunol Res."},{"issue":"2","key":"2021092315292420400_B39","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1073\/pnas.0237127100","article-title":"CTCF functions as a critical regulator of cell-cycle arrest and death after ligation of the B cell receptor on immature B cells","volume":"100","author":"Qi","year":"2003","journal-title":"Proc Natl Acad Sci USA."},{"issue":"5","key":"2021092315292420400_B40","doi-asserted-by":"crossref","first-page":"3479","DOI":"10.1074\/jbc.275.5.3479","article-title":"Cyclin D3 compensates for loss of cyclin D2 in mouse B-lymphocytes activated via the antigen receptor and CD40","volume":"275","author":"Lam","year":"2000","journal-title":"J Biol Chem."},{"issue":"10","key":"2021092315292420400_B41","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0145-2126(03)00028-6","article-title":"Influence of CD40 ligation on survival and apoptosis of B-CLL cells in vitro","volume":"27","author":"Grdisa","year":"2003","journal-title":"Leuk Res."},{"issue":"1","key":"2021092315292420400_B42","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/sj.leu.2404417","article-title":"The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease","volume":"21","author":"Longo","year":"2007","journal-title":"Leukemia."},{"issue":"7","key":"2021092315292420400_B43","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1038\/leu.2012.44","article-title":"The miR-17\u223c92 family regulates the response to Toll-like receptor 9 triggering of CLL cells with unmutated IGHV genes","volume":"26","author":"Bomben","year":"2012","journal-title":"Leukemia."},{"issue":"1","key":"2021092315292420400_B44","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3324\/haematol.2019.239947","article-title":"Genomic arrays identify high-risk chronic lymphocytic leukemia with genomic complexity: a multi-center study","volume":"106","author":"Leeksma","year":"2021","journal-title":"Haematologica."},{"issue":"24","key":"2021092315292420400_B45","doi-asserted-by":"crossref","first-page":"4902","DOI":"10.1182\/blood-2013-02-486209","article-title":"Association between molecular lesions and specific B-cell receptor subsets in chronic lymphocytic leukemia","volume":"121","author":"Rossi","year":"2013","journal-title":"Blood."},{"issue":"23","key":"2021092315292420400_B46","doi-asserted-by":"crossref","first-page":"3580","DOI":"10.1182\/blood-2014-09-603217","article-title":"Excessive antigen reactivity may underlie the clinical aggressiveness of chronic lymphocytic leukemia stereotyped subset #8","volume":"125","author":"Gounari","year":"2015","journal-title":"Blood."},{"issue":"10","key":"2021092315292420400_B47","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1084\/jem.20011866","article-title":"The B cell antigen receptor controls integrin activity through Btk and PLCgamma2","volume":"198","author":"Spaargaren","year":"2003","journal-title":"J Exp Med."},{"issue":"2","key":"2021092315292420400_B48","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1084\/jem.20171288","article-title":"Functional and clinical relevance of VLA-4 (CD49d\/CD29) in ibrutinib-treated chronic lymphocytic leukemia","volume":"215","author":"Tissino","year":"2018","journal-title":"J Exp Med."},{"issue":"5","key":"2021092315292420400_B49","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1182\/blood.2020005734","article-title":"Active AKT signaling triggers CLL towards Richter's transformation via over-activation of Notch1","volume":"137","author":"Kohlhaas","year":"2021","journal-title":"Blood."},{"issue":"20","key":"2021092315292420400_B50","doi-asserted-by":"crossref","first-page":"6260","DOI":"10.1158\/1078-0432.CCR-19-0273","article-title":"E\u03bc-TCL1xMyc: a novel mouse model for concurrent CLL and B-cell Lymphoma","volume":"25","author":"Lucas","year":"2019","journal-title":"Clin Cancer Res."},{"issue":"1","key":"2021092315292420400_B51","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/s41467-017-00830-y","article-title":"NFAT2 is a critical regulator of the anergic phenotype in chronic lymphocytic leukaemia","volume":"8","author":"M\u00e4rklin","year":"2017","journal-title":"Nat Commun."},{"issue":"1","key":"2021092315292420400_B52","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/s41467-017-00210-6","article-title":"Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia","volume":"8","author":"Knittel","year":"2017","journal-title":"Nat Commun."},{"key":"2021092315292420400_B53","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1182\/asheducation-2018.1.256","article-title":"Richter transformation in the era of novel agents","volume":"2018","author":"Ding","year":"2018","journal-title":"Hematology Am Soc Hematol Educ Program."},{"issue":"12","key":"2021092315292420400_B54","doi-asserted-by":"crossref","first-page":"3391","DOI":"10.1182\/blood-2010-09-302174","article-title":"The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation","volume":"117","author":"Rossi","year":"2011","journal-title":"Blood."},{"issue":"10","key":"2021092315292420400_B55","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1182\/blood-2014-12-610782","article-title":"The efficacy of ibrutinib in the treatment of Richter syndrome","volume":"125","author":"Tsang","year":"2015","journal-title":"Blood."},{"issue":"1","key":"2021092315292420400_B56","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1111\/bjh.15440","article-title":"BCR kinase inhibitors, idelalisib and ibrutinib, are active and effective in Richter syndrome","volume":"185","author":"Visentin","year":"2019","journal-title":"Br J Haematol."},{"issue":"22","key":"2021092315292420400_B57","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1182\/blood.V128.22.60.60","article-title":"Acalabrutinib monotherapy in patients with Richter transformation from the phase 1\/2 ACE-CL-001 clinical study [abstract]","volume":"128","author":"Hillmen","year":"2016","journal-title":"Blood."},{"issue":"11","key":"2021092315292420400_B58","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1182\/blood-2018-11-886457","article-title":"A phase 1 trial of ibrutinib plus palbociclib in previously treated mantle cell lymphoma [published correction appears in Blood. 2019;134(11):908]","volume":"133","author":"Martin","year":"2019","journal-title":"Blood."},{"issue":"5","key":"2021092315292420400_B59","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41591-018-0016-8","article-title":"Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes [published corrections appear in Nat Med. 2018;24(8):1292 and Nat Med. 2018;24(8):1290\u20131291]","volume":"24","author":"Chapuy","year":"2018","journal-title":"Nat Med."},{"issue":"4","key":"2021092315292420400_B60","doi-asserted-by":"crossref","first-page":"700","DOI":"10.2144\/96214rr03","article-title":"Substrate nucleotide-determined non-templated addition of adenine by Taq DNA polymerase: implications for PCR-based genotyping and cloning","volume":"21","author":"Magnuson","year":"1996","journal-title":"Biotechniques."},{"issue":"2","key":"2021092315292420400_B61","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","article-title":"Drug combination studies and their synergy quantification using the Chou-Talalay method","volume":"70","author":"Chou","year":"2010","journal-title":"Cancer Res."}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/138\/12\/1053\/1823669\/bloodbld2020008276.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/138\/12\/1053\/1823669\/bloodbld2020008276.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,25]],"date-time":"2022-12-25T12:54:55Z","timestamp":1671972895000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/138\/12\/1053\/475837\/B-cell-receptor-signaling-and-genetic-lesions-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,28]]},"references-count":61,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,4,28]]},"published-print":{"date-parts":[[2021,9,23]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2020008276","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,28]]}}}