Rachel Thijssen, Sarah T Diepstraten, Donia M Moujalled, Edward Chew, Christoffer Flensburg, Melissa Xiaoqing Shi, Michael A Dengler, Veronique Litalien, Sarah MacRaild, Maoshan Chen, Natasha S Anstee, Boris Reljic, Sarah S Gabriel, Tirta M Djajawi, Chris D Riffkin, Brandon James Aubrey, Catherine Chang, Lin Tai, Zhen Xu, Thomas David Morley, Giovanna Pomilio, Claudia Bruedigam, Axel Kallies, David A Stroud, Ashish Bajel, Ruth M Kluck, Steven W Lane, Marie Schoumacher, Sébastien Banquet, Ian J Majewski, Andreas Strasser, Andrew W Roberts, David Ching Siang Huang, Fiona C Brown, Gemma Kelly, Andrew H Wei
Selective targeting of BCL2 with the BH3-mimetic venetoclax is proving transformative for patients with various leukemias. TP53 controls apoptosis upstream from where BCL2 and its pro-survival relatives, such as MCL1, act. Therefore, targeting these pro-survival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL2 has produced clinically relevant responses in blood cancers with aberrant TP53. However, we show that TP53 mutated or deficient myeloid and lymphoid leukemias outcompete isogenic controls with intact TP53, unless sufficient concentrations of BH3-mimetics targeting BCL2 or MCL1 are applied...
April 6, 2021: Blood