Ways to increase the anti-multiple myeloma (MM) efficacy of proteasome inhibitors (PI) are needed to improve therapeutic responses, disease-free survival, and bone health in MM patients. Through in vitro and in vivo experiments, Marino and colleagues studied the activity of a small molecule ligand of the ZZ-domain, XRK3F2, that decreased osteoclast formation and activity, and reversed MM-epigenetic suppression of osteoblast differentiation. They showed that XRK3F2 boosts both the anti-tumor and bone-anabolic effects of PI and provide a strong rationale for developing a new therapeutic regimen based on co-administration of XRK3F2 and bortezomib to treat MM.

Venetoclax-containing regimens, which are standard of care for unfit patients with acute myeloid leukemia (AML), are associated with high incidences of clinically relevant cytopenias. The underlying cause of these cytopenias is unexplained, and the lack of venetoclax effect on BCL2 expression in mature hematopoietic lineages suggests that the observed cytopenias are driven by changes in non-malignant hematopoietic stem and progenitor cells (HSPC). With their research, Fowler-Shorten and colleagues show that AML induces an IL-3-dependent upregulation of BCL2 in HSPC, which in turn increases HSPC sensitivity to venetoclax and causes cytopenias.