Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division.

Aneuploidy, defined as whole chromosome gains and losses, is associated with poor patient prognosis in many cancer types. However, the condition causes cellular stress and cell cycle delays, foremost in G1 and S phase. Here, we investigate how aneuploidy causes both slow proliferation and poor disease outcome.

Prediction of venetoclax activity in precursor B-ALL by functional assessment of apoptosis signaling.

Deregulated cell death pathways contribute to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Intrinsic apoptosis signaling is regulated by different proapoptotic and antiapoptotic molecules: proapoptotic BCL-2 homology domain 3 (BH3) proteins activate prodeath molecules leading to cellular death, while antiapoptotic molecules including B-cell lymphoma 2 (BCL-2) prevent activation of prodeath proteins and counter-regulate apoptosis induction. Inhibition of these antiapoptotic regulators has become a promising strategy for anticancer treatment, but variable anticancer activities in different malignancies indicate the need for upfront identification of responsive patients.

BH3 profiling discriminates on-target small molecule BH3 mimetics from putative mimetics.

Inhibition of the anti-apoptotic machinery of cancer cells is a promising therapeutic approach that has driven the development of an important class of compounds termed "BH3 mimetics". These novel small molecules mimic BH3-only proteins by antagonizing the pro-survival function of anti-apoptotic proteins, thereby inducing apoptosis in cancer cells. To qualify as an authentic BH3 mimetic, a compound must function directly on the mitochondria of a cell of known anti-apoptotic dependence, must directly and selectively inhibit the anti-apoptotic protein with high-affinity binding, and must induce mitochondrial outer membrane permeabilization (MOMP) and apoptosis in a BAX/BAK-dependent manner.

Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL.

Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/phosphoinositide 3-kinase (PI3K) signaling and dysregulated B-cell lymphoma 2 (BCL-2) expression.