biostudies-literatureThijssen RSwiss National Science Foundation2721-2735https://www.ebi.ac.uk/biostudies/studies/S-EPMC8138548biostudies-literatureUnknown137(20)Selective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemias. TP-53 controls apoptosis upstream of where BCL-2 and its prosurvival relatives, such as MCL-1, act. Therefore, targeting these prosurvival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL-2 has produced clinically relevant responses in blood cancers with aberrant TP-53. However, in our study, TP53-mutated or -deficient myeloid and lymphoid leukemias outcompeted isogenic controls with intact TP-53, unless sufficient concentrations of BH3-mimetics targeting BCL-2 or MCL-1 were applied. Strikingly, tumor cells with TP-53 dysfunction escaped and thrived over time if inhibition of BCL-2 or BloodIntact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias.PMC8138548180807Litalien VKallies APomilio GReljic BGabriel SSStrasser AMacRaild SRiffkin CDDjajawi TMBajel AMajewski IJWei AHChang CSchoumacher MMorley TChew EMoujalled DLane SWKelly GLTai LDiepstraten STDengler MAChen MThijssen RAnstee NSAubrey BJBruedigam CBanquet SHuang DCSStroud DABrown FCShi MXKluck RMFlensburg CXu ZRoberts AWfalseIntact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias.Selective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemias. TP-53 controls apoptosis upstream of where BCL-2 and its prosurvival relatives, such as MCL-1, act. Therefore, targeting these prosurvival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL-2 has produced clinically relevant responses in blood cancers with aberrant TP-53. However, in our study, TP53-mutated or -deficient myeloid and lymphoid leukemias outcompeted isogenic controls with intact TP-53, unless sufficient concentrations of BH3-mimetics targeting BCL-2 or MCL-1 were applied. Strikingly, tumor cells with TP-53 dysfunction escaped and thrived over time if inhibition of BCL-2 or 2021-01-01T00:00:00Z2021 May2026-06-11T04:03:45.863Z2022-02-11T14:14:48.64ZS-EPMC81385483382497510.1182/blood.2020010167