Both BCL-2 and BCL-XL are validated therapeutic targets in a wide range of hematologic cancers, including acute myeloid leukemia. Moreover, BCL-XL is a mediator of chemo- and venetoclax-resistance. The first-in-class dual BCL-XL/BCL-2 proteolysis-targeting chimera (PROTAC) 753B selectively induces both BCL-XL and BCL-2 ubiquitination and degradation in cells expressing von Hippel-Landau (VHL). In their study, Jia and colleagues demonstrate that 753B effectively eliminates leukemia cells in vitro and in vivo, and enhances chemotherapy efficacy by targeting senescent cells.

Hemizygous deletion of the long arm of chromosome 5q (del(5q)) is the most common cytogenetic alteration in myelodysplastic syndromes (MDS). The effects of low-grade inflammatory signals on hematopoietic stem and progenitorcells (HPSC) and del(5q) MDS progression remains uncharacterized. In their study, Muto and colleagues, using a mouse model, show that low-grade inflammation suppresses del(5q) MDS HSPC via p53, providing a potential explanation for the high grade of TP53 mutations in patients with del(5q) MDS.