{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T17:11:53Z","timestamp":1789924313634,"version":"4.0.1"},"reference-count":62,"publisher":"American Society of Hematology","issue":"15","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,10,10]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>T-prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm associated with marked chemotherapy resistance and continued poor clinical outcomes. Current treatments, that is, the CD52-antibody alemtuzumab, offer transient responses, with relapses being almost inevitable without consolidating allogeneic transplantation. Recent more detailed concepts of T-PLL\u2019s pathobiology fostered the identification of actionable vulnerabilities: (1) altered epigenetics, (2) defective DNA damage responses, (3) aberrant cell-cycle regulation, and (4) deregulated prosurvival pathways, including T-cell receptor and JAK\/STAT signaling. To further develop related preclinical therapeutic concepts, we studied inhibitors of histone deacetylases ([H]DACs), B-cell lymphoma 2 (BCL2), cyclin-dependent kinase (CDK), mouse double minute 2 (MDM2), and classical cytostatics, using (1) single-agent and combinatorial compound testing in 20 well-characterized and molecularly profiled primary T-PLL (validated by additional 42 cases) and (2) 2 independent murine models (syngeneic transplants and patient-derived xenografts). Overall, the most efficient\/selective single agents and combinations (in\u00a0vitro and in mice) included cladribine, romidepsin ([H]DAC), venetoclax (BCL2), and\/or idasanutlin (MDM2). Cladribine sensitivity correlated with expression of its target RRM2. T-PLL cells revealed low overall apoptotic priming with heterogeneous dependencies on BCL2 proteins. In additional 38 T-cell leukemia\/lymphoma lines, TP53 mutations were associated with resistance toward MDM2 inhibitors. P53 of T-PLL cells, predominantly in wild-type configuration, was amenable to MDM2 inhibition, which increased its MDM2-unbound fraction. This facilitated P53 activation and downstream signals (including enhanced accessibility of target-gene chromatin regions), in particular synergy with insults by cladribine. Our data emphasize the therapeutic potential of pharmacologic strategies to reinstate P53-mediated apoptotic responses. The identified efficacies and their synergies provide an informative background on compound and patient selection for trial designs in T-PLL.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2023022884","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T20:50:57Z","timestamp":1719607857000},"page":"1595-1610","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":13,"title":["Optimizing drug combinations for T-PLL: restoring DNA damage and P53-mediated apoptotic responses"],"prefix":"10.1182","volume":"144","author":[{"given":"Jana","family":"von Jan","sequence":"first","affiliation":[{"name":"1Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, University Hospital Cologne, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany"},{"name":"3Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8139-5950","authenticated-orcid":false,"given":"Sanna","family":"Timonen","sequence":"additional","affiliation":[{"name":"4Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland"},{"name":"5Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland"},{"name":"6Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Till","family":"Braun","sequence":"additional","affiliation":[{"name":"1Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, University Hospital Cologne, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany"},{"name":"3Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8517-7750","authenticated-orcid":false,"given":"Qu","family":"Jiang","sequence":"additional","affiliation":[{"name":"1Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, University Hospital Cologne, University of Cologne, Cologne, Germany"},{"name":"2Cologne Excellence Cluster on Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany"},{"name":"3Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany"},{"name":"7Department of Hematology, Cellular Therapy, Hemostaseology, Infectious Diseases, University Hospital Leipzig, 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