{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T19:36:11Z","timestamp":1791401771733,"version":"4.3.3"},"reference-count":68,"publisher":"American Society of Hematology","issue":"20","license":[{"start":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T00:00:00Z","timestamp":1655251200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,11,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)\/CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter\u2019s syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in\u00a0vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.<\/jats:p>","DOI":"10.1182\/blood.2021014304","type":"journal-article","created":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T14:53:05Z","timestamp":1655304785000},"page":"2113-2126","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":108,"title":["Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies"],"prefix":"10.1182","volume":"140","author":[{"given":"D.","family":"Thomalla","sequence":"first","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5207-8991","authenticated-orcid":false,"given":"L.","family":"Beckmann","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4676-8870","authenticated-orcid":false,"given":"C.","family":"Grimm","sequence":"additional","affiliation":[{"name":"3Institute for Translational Epigenetics, Medical Faculty, University of Cologne, Cologne, Germany"},{"name":"4Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7969-2796","authenticated-orcid":false,"given":"M.","family":"Oliverio","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Meder","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"},{"name":"5Mildred Scheel School of Oncology Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. D.","family":"Herling","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany"},{"name":"6Clinic of Hematology, Cellular Therapy and Hemostaseology, University of Leipzig, Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Nieper","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.","family":"Feldmann","sequence":"additional","affiliation":[{"name":"3Institute for Translational Epigenetics, Medical Faculty, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O.","family":"Merkel","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Lorsy","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"da Palma Guerreiro","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"von Jan","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6207-3991","authenticated-orcid":false,"given":"I.","family":"Kisis","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Wasserburger","sequence":"additional","affiliation":[{"name":"3Institute for Translational Epigenetics, Medical Faculty, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Claasen","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Faitschuk-Meyer","sequence":"additional","affiliation":[{"name":"7Miltenyi Biotec B.V. & Co. KG, Bergisch-Gladbach, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4372-1521","authenticated-orcid":false,"given":"J.","family":"Altm\u00fcller","sequence":"additional","affiliation":[{"name":"4Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7228-428X","authenticated-orcid":false,"given":"P.","family":"N\u00fcrnberg","sequence":"additional","affiliation":[{"name":"4Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany"},{"name":"8Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T.-P.","family":"Yang","sequence":"additional","affiliation":[{"name":"8Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany"},{"name":"9Center of Integrated Oncology Cologne-Bonn, Medical Faculty, Department of Translational Genomics, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2549-3142","authenticated-orcid":false,"given":"M.","family":"Lienhard","sequence":"additional","affiliation":[{"name":"10Department of Computational Molecular Biology, Max-Planck-Institute for Molecular Genetics, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9335-1760","authenticated-orcid":false,"given":"R.","family":"Herwig","sequence":"additional","affiliation":[{"name":"10Department of Computational Molecular Biology, Max-Planck-Institute for Molecular Genetics, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.-A.","family":"Kreuzer","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. P.","family":"Pallasch","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"B\u00fcttner","sequence":"additional","affiliation":[{"name":"11Department of Pathology, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2116-1212","authenticated-orcid":false,"given":"S. C.","family":"Sch\u00e4fer","sequence":"additional","affiliation":[{"name":"11Department of Pathology, University of Cologne, Cologne, Germany"},{"name":"12Institut f\u00fcr Pathologie im Medizin Campus Bodensee, Friedrichshafen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Hartley","sequence":"additional","affiliation":[{"name":"13RCI, Regensburg Center for Interventional Immunology, University Hospital of Regensburg, Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4302-3240","authenticated-orcid":false,"given":"H.","family":"Abken","sequence":"additional","affiliation":[{"name":"13RCI, Regensburg Center for Interventional Immunology, University Hospital of Regensburg, Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5243-5503","authenticated-orcid":false,"given":"M.","family":"Peifer","sequence":"additional","affiliation":[{"name":"8Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany"},{"name":"9Center of Integrated Oncology Cologne-Bonn, Medical Faculty, Department of Translational Genomics, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Kashkar","sequence":"additional","affiliation":[{"name":"2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany"},{"name":"8Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany"},{"name":"14Institute for Molecular Immunologie, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8395-3701","authenticated-orcid":false,"given":"G.","family":"Knittel","sequence":"additional","affiliation":[{"name":"15Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, German Cancer Consortium (DKTK Partner Site Essen), Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Eichhorst","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. T.","family":"Ullrich","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"},{"name":"8Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Herling","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany"},{"name":"6Clinic of Hematology, Cellular Therapy and Hemostaseology, University of Leipzig, Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. C.","family":"Reinhardt","sequence":"additional","affiliation":[{"name":"15Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, German Cancer Consortium (DKTK Partner Site Essen), Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Hallek","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. R.","family":"Schweiger","sequence":"additional","affiliation":[{"name":"3Institute for Translational Epigenetics, Medical Faculty, University of Cologne, Cologne, Germany"},{"name":"4Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany"},{"name":"8Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. P.","family":"Frenzel","sequence":"additional","affiliation":[{"name":"1Faculty of Medicine and Cologne University Hospital, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"23","key":"2022111716253835800_bib1","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1056\/NEJMoa1815281","article-title":"Venetoclax and obinutuzumab in patients with CLL and coexisting conditions","volume":"380","author":"Fischer","year":"2019","journal-title":"N\u00a0Engl J Med"},{"issue":"22","key":"2022111716253835800_bib2","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1056\/NEJMoa1900574","article-title":"Ibrutinib and venetoclax for first-line treatment of CLL","volume":"380","author":"Jain","year":"2019","journal-title":"N\u00a0Engl J Med"},{"issue":"13","key":"2022111716253835800_bib3","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1056\/NEJMoa1715519","article-title":"Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma","volume":"378","author":"Tam","year":"2018","journal-title":"N\u00a0Engl J Med"},{"issue":"4","key":"2022111716253835800_bib4","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1056\/NEJMoa1513257","article-title":"Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia","volume":"374","author":"Roberts","year":"2016","journal-title":"N\u00a0Engl J Med"},{"issue":"9","key":"2022111716253835800_bib5","doi-asserted-by":"crossref","first-page":"e404","DOI":"10.3324\/haematol.2018.188094","article-title":"Efficacy of the combination of venetoclax and hypomethylating agents in relapsed\/refractory acute myeloid leukemia","volume":"103","author":"Aldoss","year":"2018","journal-title":"Haematologica"},{"issue":"9","key":"2022111716253835800_bib6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/10428194.2017.1283032","article-title":"Pathways and mechanisms of venetoclax resistance","volume":"58","author":"Bose","year":"2017","journal-title":"Leuk Lymphoma"},{"issue":"1","key":"2022111716253835800_bib7","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1182\/blood-2018-08-868752","article-title":"Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia","volume":"133","author":"DiNardo","year":"2019","journal-title":"Blood"},{"issue":"26","key":"2022111716253835800_bib8","doi-asserted-by":"crossref","first-page":"4111","DOI":"10.1182\/blood-2014-03-560284","article-title":"Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma","volume":"123","author":"Fresquet","year":"2014","journal-title":"Blood"},{"issue":"8","key":"2022111716253835800_bib9","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1182\/blood.2021012775","article-title":"Clonal hematopoiesis, myeloid disorders and BAX-mutated myelopoiesis in patients receiving venetoclax for CLL","volume":"139","author":"Blombery","year":"2022","journal-title":"Blood"},{"issue":"3","key":"2022111716253835800_bib10","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1158\/2159-8290.CD-18-1119","article-title":"Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia","volume":"9","author":"Blombery","year":"2019","journal-title":"Cancer Discov"},{"issue":"6","key":"2022111716253835800_bib11","doi-asserted-by":"crossref","first-page":"e188","DOI":"10.1111\/bjh.16069","article-title":"Characterization of a novel venetoclax resistance mutation (BCL2 Phe104Ile) observed in follicular lymphoma","volume":"186","author":"Blombery","year":"2019","journal-title":"Br J Haematol"},{"issue":"9","key":"2022111716253835800_bib12","doi-asserted-by":"crossref","first-page":"e434","DOI":"10.3324\/haematol.2019.222588","article-title":"Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia","volume":"104","author":"Tausch","year":"2019","journal-title":"Haematologica"},{"issue":"1","key":"2022111716253835800_bib13","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/s41467-018-03170-7","article-title":"Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia","volume":"9","author":"Herling","year":"2018","journal-title":"Nat Commun"},{"issue":"11","key":"2022111716253835800_bib14","doi-asserted-by":"crossref","first-page":"e540","DOI":"10.3324\/haematol.2019.232835","article-title":"Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia (Comment to Tausch et\u00a0al)","volume":"104","author":"Weiss","year":"2019","journal-title":"Haematologica"},{"issue":"1","key":"2022111716253835800_bib15","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/cdd.2017.161","article-title":"The BCL-2 arbiters of apoptosis and their growing role as cancer targets","volume":"25","author":"Adams","year":"2018","journal-title":"Cell Death Differ"},{"issue":"15","key":"2022111716253835800_bib16","doi-asserted-by":"crossref","first-page":"5204","DOI":"10.1158\/0008-5472.CAN-10-4531","article-title":"Akt-dependent glucose metabolism promotes Mcl-1 synthesis to maintain cell survival and resistance to Bcl-2 inhibition","volume":"71","author":"Coloff","year":"2011","journal-title":"Cancer Res"},{"issue":"8","key":"2022111716253835800_bib17","first-page":"e302","article-title":"Resistance to ABT-199 induced by microenvironmental signals in chronic lymphocytic leukemia can be counteracted by CD20 antibodies or kinase inhibitors","volume":"100","author":"Thijssen","year":"2015","journal-title":"Haematologica"},{"issue":"4","key":"2022111716253835800_bib18","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1038\/leu.2014.320","article-title":"Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia","volume":"29","author":"Huelsemann","year":"2015","journal-title":"Leukemia"},{"issue":"4","key":"2022111716253835800_bib19","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.ccell.2019.08.005","article-title":"Mitochondrial reprogramming underlies resistance to BCL-2 inhibition in lymphoid malignancies","volume":"36","author":"Gui\u00e8ze","year":"2019","journal-title":"Cancer Cell"},{"issue":"17","key":"2022111716253835800_bib20","doi-asserted-by":"crossref","first-page":"2692","DOI":"10.4161\/cc.8.17.9412","article-title":"PUMA cooperates with direct activator proteins to promote mitochondrial outer membrane permeabilization and apoptosis","volume":"8","author":"Chipuk","year":"2009","journal-title":"Cell Cycle"},{"issue":"6","key":"2022111716253835800_bib21","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1093\/nar\/25.6.1317","article-title":"B\u00a0lymphocyte-specific, Cre-mediated mutagenesis in mice","volume":"25","author":"Rickert","year":"1997","journal-title":"Nucleic Acids Res"},{"issue":"10","key":"2022111716253835800_bib22","doi-asserted-by":"crossref","first-page":"6955","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"},{"issue":"32","key":"2022111716253835800_bib23","doi-asserted-by":"crossref","first-page":"11272","DOI":"10.1073\/pnas.0504783102","article-title":"Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease","volume":"102","author":"Takeuchi","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"issue":"7","key":"2022111716253835800_bib24","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1182\/blood.2020009165","article-title":"MARCKS affects cell motility and response to BTK inhibitors in CLL","volume":"138","author":"Beckmann","year":"2021","journal-title":"Blood"},{"issue":"19","key":"2022111716253835800_bib25","doi-asserted-by":"crossref","first-page":"2948","DOI":"10.1182\/blood-2014-07-586511","article-title":"miRs-138 and -424 control palmitoylation-dependent CD95-mediated cell death by targeting acyl protein thioesterases 1 and 2 in CLL","volume":"125","author":"Berg","year":"2015","journal-title":"Blood"},{"issue":"4","key":"2022111716253835800_bib26","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.cell.2018.11.044","article-title":"Genome-wide CRISPR screens in T helper cells reveal pervasive crosstalk between activation and differentiation","volume":"176","author":"Henriksson","year":"2019","journal-title":"Cell"},{"issue":"8","key":"2022111716253835800_bib27","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/ng1598","article-title":"Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells","volume":"37","author":"Weber","year":"2005","journal-title":"Nat Genet"},{"issue":"10","key":"2022111716253835800_bib28","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1093\/bioinformatics\/btu049","article-title":"Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays","volume":"30","author":"Aryee","year":"2014","journal-title":"Bioinformatics"},{"issue":"6","key":"2022111716253835800_bib29","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1073\/pnas.1009069108","article-title":"Eradication of melanomas by targeted elimination of a minor subset of tumor cells","volume":"108","author":"Schmidt","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"issue":"2","key":"2022111716253835800_bib30","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/sj.gt.3300813","article-title":"A\u00a0chimeric receptor that selectively targets membrane-bound carcinoembryonic antigen (mCEA) in the presence of soluble CEA","volume":"6","author":"Hombach","year":"1999","journal-title":"Gene Ther"},{"issue":"4","key":"2022111716253835800_bib31","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1182\/blood-2002-07-1989","article-title":"T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect","volume":"101","author":"Cooper","year":"2003","journal-title":"Blood"},{"issue":"1","key":"2022111716253835800_bib32","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1158\/2643-3230.BCD-19-0059","article-title":"An autochthonous mouse model of Myd88- and BCL2-driven diffuse large B-cell lymphoma reveals actionable molecular vulnerabilities","volume":"2","author":"Fl\u00fcmann","year":"2021","journal-title":"Blood Cancer Discov"},{"issue":"22","key":"2022111716253835800_bib33","doi-asserted-by":"crossref","first-page":"2732","DOI":"10.1182\/blood-2015-11-684183","article-title":"German International Cancer Genome Consortium Molecular Mechanisms in Malignant Lymphoma by Sequencing Project Consortium. B-cell-specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice","volume":"127","author":"Knittel","year":"2016","journal-title":"Blood"},{"issue":"19","key":"2022111716253835800_bib34","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.1200\/JCO.2017.76.6840","article-title":"Venetoclax for patients with chronic lymphocytic leukemia with 17p Deletion: results from the full population of a phase II pivotal trial","volume":"36","author":"Stilgenbauer","year":"2018","journal-title":"J\u00a0Clin Oncol"},{"issue":"3","key":"2022111716253835800_bib35","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1038\/leu.2017.252","article-title":"Discovery of novel drug sensitivities in T-PLL by high-throughput ex\u00a0vivo drug testing and mutation profiling","volume":"32","author":"Andersson","year":"2018","journal-title":"Leukemia"},{"issue":"23","key":"2022111716253835800_bib36","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1182\/blood-2017-05-785683","article-title":"First-in-human response of BCL-2 inhibitor venetoclax in T-cell prolymphocytic leukemia","volume":"130","author":"Boidol","year":"2017","journal-title":"Blood"},{"issue":"4","key":"2022111716253835800_bib37","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1309\/JQ2X3RV3L8F9TGYW","article-title":"Role of bax mutations in apoptosis in colorectal cancers with microsatellite instability","volume":"123","author":"Miquel","year":"2005","journal-title":"Am J Clin Pathol"},{"issue":"5302","key":"2022111716253835800_bib38","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1126\/science.275.5302.967","article-title":"Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype","volume":"275","author":"Rampino","year":"1997","journal-title":"Science"},{"issue":"7626","key":"2022111716253835800_bib39","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nature19830","article-title":"The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models","volume":"538","author":"Kotschy","year":"2016","journal-title":"Nature"},{"issue":"8","key":"2022111716253835800_bib40","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.3324\/haematol.2019.220525","article-title":"Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma","volume":"105","author":"Smith","year":"2020","journal-title":"Haematologica"},{"issue":"1","key":"2022111716253835800_bib41","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"},{"issue":"5","key":"2022111716253835800_bib42","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1182\/blood.2020005734","article-title":"Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1","volume":"137","author":"Kohlhaas","year":"2021","journal-title":"Blood"},{"issue":"9","key":"2022111716253835800_bib43","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.bcp.2011.07.064","article-title":"Mcl-1 downregulation by YM155 contributes to its\u00a0synergistic anti-tumor activities with ABT-263","volume":"82","author":"Tang","year":"2011","journal-title":"Biochem Pharmacol"},{"issue":"7784","key":"2022111716253835800_bib44","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/s41586-019-1770-6","article-title":"Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis","volume":"575","author":"Fritsch","year":"2019","journal-title":"Nature"},{"issue":"18","key":"2022111716253835800_bib45","doi-asserted-by":"crossref","first-page":"3667","DOI":"10.1038\/emboj.2011.307","article-title":"Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases","volume":"30","author":"Strasser","year":"2011","journal-title":"EMBO J"},{"issue":"17","key":"2022111716253835800_bib46","doi-asserted-by":"crossref","first-page":"5391","DOI":"10.1128\/MCB.00907-07","article-title":"Selection against PUMA gene expression in Myc-driven B-cell lymphomagenesis","volume":"28","author":"Garrison","year":"2008","journal-title":"Mol Cell Biol"},{"issue":"4","key":"2022111716253835800_bib47","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/S1535-6108(03)00244-7","article-title":"Puma is an essential mediator of p53-dependent and -independent apoptotic pathways","volume":"4","author":"Jeffers","year":"2003","journal-title":"Cancer Cell"},{"issue":"445","key":"2022111716253835800_bib48","doi-asserted-by":"crossref","first-page":"eaaq1240","DOI":"10.1126\/scitranslmed.aaq1240","article-title":"Statins enhance efficacy of venetoclax in blood cancers","volume":"10","author":"Lee","year":"2018","journal-title":"Sci Transl Med"},{"issue":"441","key":"2022111716253835800_bib49","doi-asserted-by":"crossref","first-page":"eaao4680","DOI":"10.1126\/scitranslmed.aao4680","article-title":"Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma","volume":"10","author":"Lochmann","year":"2018","journal-title":"Sci Transl Med"},{"issue":"5","key":"2022111716253835800_bib50","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1158\/2159-8290.CD-20-1065","article-title":"Endogenous retroelement activation by epigenetic therapy reverses the Warburg effect and elicits mitochondrial-mediated cancer cell death","volume":"11","author":"Fresquet","year":"2021","journal-title":"Cancer Discov"},{"issue":"2","key":"2022111716253835800_bib51","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.ccell.2018.12.012","article-title":"Wild-type p53 Promotes cancer metabolic switch by inducing PUMA-dependent suppression of oxidative phosphorylation","volume":"35","author":"Kim","year":"2019","journal-title":"Cancer Cell"},{"issue":"4","key":"2022111716253835800_bib52","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1002\/hep.24516","article-title":"PUMA-mediated apoptosis drives chemical hepatocarcinogenesis in mice","volume":"54","author":"Qiu","year":"2011","journal-title":"Hepatology"},{"issue":"4","key":"2022111716253835800_bib53","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/cdd.2008.179","article-title":"Puma indirectly activates Bax to cause apoptosis in the absence of Bid or Bim","volume":"16","author":"Jabbour","year":"2009","journal-title":"Cell Death Differ"},{"issue":"1","key":"2022111716253835800_bib54","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1186\/s12885-017-3383-5","article-title":"Potential mechanisms of resistance to venetoclax and strategies to circumvent it","volume":"17","author":"Tahir","year":"2017","journal-title":"BMC Cancer"},{"issue":"3","key":"2022111716253835800_bib55","doi-asserted-by":"crossref","first-page":"697","DOI":"10.3324\/haematol.2018.205534","article-title":"Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models","volume":"105","author":"Han","year":"2020","journal-title":"Haematologica"},{"issue":"1","key":"2022111716253835800_bib56","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41392-021-00870-3","article-title":"Activation of RAS\/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia","volume":"7","author":"Zhang","year":"2022","journal-title":"Signal Transduct Target Ther"},{"issue":"43","key":"2022111716253835800_bib57","doi-asserted-by":"crossref","first-page":"70000","DOI":"10.18632\/oncotarget.12132","article-title":"Acquired resistance to venetoclax (ABT-199) in t(14;18) positive lymphoma cells","volume":"7","author":"Bodo","year":"2016","journal-title":"Oncotarget"},{"issue":"1","key":"2022111716253835800_bib58","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/s41375-018-0201-2","article-title":"The MCL1-specific inhibitor S63845 acts synergistically with venetoclax\/ABT-199 to induce apoptosis in T-cell acute lymphoblastic leukemia cells","volume":"33","author":"Li","year":"2019","journal-title":"Leukemia"},{"issue":"2","key":"2022111716253835800_bib59","doi-asserted-by":"crossref","first-page":"E47","DOI":"10.1002\/ajh.26411","article-title":"Identification of recurrent genomic alterations in the apoptotic machinery in chronic lymphocytic leukemia patients treated with venetoclax monotherapy","volume":"97","author":"Popovic","year":"2022","journal-title":"Am J Hematol"},{"issue":"2","key":"2022111716253835800_bib60","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1182\/bloodadvances.2021006211","article-title":"Single-cell sequencing demonstrates complex resistance landscape in CLL and MCL treated with BTK and BCL2 inhibitors","volume":"6","author":"Thompson","year":"2022","journal-title":"Blood Adv"},{"issue":"7","key":"2022111716253835800_bib61","doi-asserted-by":"crossref","first-page":"2330","DOI":"10.1002\/cam4.2870","article-title":"Microsatellite instability and its associations with the clinicopathologic characteristics of diffuse large B-cell lymphoma","volume":"9","author":"Tian","year":"2020","journal-title":"Cancer Med"},{"issue":"8","key":"2022111716253835800_bib62","doi-asserted-by":"crossref","first-page":"3173","DOI":"10.1182\/blood.V90.8.3173","article-title":"Prognostic significance of Bax protein expression in diffuse aggressive non-Hodgkin\u2019s lymphoma","volume":"90","author":"Gascoyne","year":"1997","journal-title":"Blood"},{"issue":"2","key":"2022111716253835800_bib63","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1002\/ajh.10333","article-title":"Prognostic significance of bcl-2, bax, and p53 expression in diffuse large B-cell lymphoma","volume":"73","author":"Sohn","year":"2003","journal-title":"Am J Hematol"},{"issue":"10","key":"2022111716253835800_bib64","first-page":"2860","article-title":"Bcl-2, Bcl-X, Bax, and Bak expression in short- and long-lived patients with diffuse large B-cell lymphomas","volume":"5","author":"Bairey","year":"1999","journal-title":"Clin Cancer Res"},{"issue":"5","key":"2022111716253835800_bib65","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1182\/blood-2018-02-830992","article-title":"A\u00a0CD19\/CD3 bispecific antibody for effective immunotherapy of chronic lymphocytic leukemia in the ibrutinib era","volume":"132","author":"Robinson","year":"2018","journal-title":"Blood"},{"issue":"1","key":"2022111716253835800_bib66","doi-asserted-by":"crossref","first-page":"e000218","DOI":"10.1136\/jitc-2019-000218","article-title":"CD3xCD19 DART molecule treatment induces non-apoptotic killing and is efficient against high-risk chemotherapy and venetoclax-resistant chronic lymphocytic leukemia cells","volume":"8","author":"Martens","year":"2020","journal-title":"J\u00a0Immunother Cancer"},{"issue":"suppl 1","key":"2022111716253835800_bib67","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1182\/blood-2018-99-111061","article-title":"Comparison of efficacy and toxicity of CD19-specific chimeric antigen receptor T-cells alone or in combination with ibrutinib for relapsed and\/or refractory CLL","volume":"132","author":"Gauthier","year":"2018","journal-title":"Blood"},{"issue":"19","key":"2022111716253835800_bib68","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1182\/blood.2019002936","article-title":"Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure","volume":"135","author":"Gauthier","year":"2020","journal-title":"Blood"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/140\/20\/2113\/1982950\/blood_bld-2021-014304-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/140\/20\/2113\/1982950\/blood_bld-2021-014304-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T11:27:27Z","timestamp":1668684447000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/140\/20\/2113\/485569\/Deregulation-and-epigenetic-modification-of-BCL2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,17]]},"references-count":68,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2022,11,17]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2021014304","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,17]]}}}