Optimizing drug combinations for T-PLL: restoring DNA damage and P53-mediated apoptotic responses

Jana von Jan, Sanna Timonen, Till Braun, Qu Jiang, Aleksandr Ianevski, Yayi Peng, Kathleen McConnell, Paola Sindaco, Tony Andreas Müller, Sabine Pützer, Hanna Klepzig, Dennis Jungherz, Annika Dechow, Linus Wahnschaffe, Anil K. Giri, Matti Kankainen, Heikki Kuusanmäki, Heidi A. Neubauer, Richard Moriggl, Paolo MazzeoNicole Schmidt, Raphael Koch, Michael Hallek, Amel Chebel, David Armisen, Laurent Genestier, Emmanuel Bachy, Anjali Mishra, Alexandra Schrader, Tero Aittokallio, Satu Mustjoki, Marco Herling

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

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's 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 vitro 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.

Originalspråkengelska
TidskriftBlood
Volym144
Nummer15
Sidor (från-till)1595–1610
Antal sidor16
ISSN0006-4971
DOI
StatusPublicerad - 2024
MoE-publikationstypA1 Tidskriftsartikel-refererad

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Publisher Copyright:
© 2024 American Society of Hematology

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  • 3121 Allmänmedicin, inre medicin och annan klinisk medicin

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