TY - JOUR
T1 - Optimizing drug combinations for T-PLL
T2 - restoring DNA damage and P53-mediated apoptotic responses
AU - von Jan, Jana
AU - Timonen, Sanna
AU - Braun, Till
AU - Jiang, Qu
AU - Ianevski, Aleksandr
AU - Peng, Yayi
AU - McConnell, Kathleen
AU - Sindaco, Paola
AU - Müller, Tony Andreas
AU - Pützer, Sabine
AU - Klepzig, Hanna
AU - Jungherz, Dennis
AU - Dechow, Annika
AU - Wahnschaffe, Linus
AU - Giri, Anil K.
AU - Kankainen, Matti
AU - Kuusanmäki, Heikki
AU - Neubauer, Heidi A.
AU - Moriggl, Richard
AU - Mazzeo, Paolo
AU - Schmidt, Nicole
AU - Koch, Raphael
AU - Hallek, Michael
AU - Chebel, Amel
AU - Armisen, David
AU - Genestier, Laurent
AU - Bachy, Emmanuel
AU - Mishra, Anjali
AU - Schrader, Alexandra
AU - Aittokallio, Tero
AU - Mustjoki, Satu
AU - Herling, Marco
N1 - Publisher Copyright:
© 2024 American Society of Hematology
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - 3121 General medicine, internal medicine and other clinical medicine
U2 - 10.1182/blood.2023022884
DO - 10.1182/blood.2023022884
M3 - Article
C2 - 38941598
AN - SCOPUS:85202974186
SN - 0006-4971
VL - 144
SP - 1595
EP - 1610
JO - Blood
JF - Blood
IS - 15
ER -