This review provides a roadmap for the targeted therapy era in ALL, defining high-risk molecular subtypes and their targeted vulnerabilities. It synthesizes advances in BH3 mimetics, menin inhibition, and immunotherapy, while addressing the critical challenges of treatment resistance and phenotypic escape that define the next frontier of research.

This study demonstrates that multiple myeloma cells in different neighborhoods experience unique metabolic conditions and immune environments, and that neighbor preference of CD4+ T cells and PCs is associated with poorer PFS. These data highlight the value of spatially resolved analyses in uncovering potential pathophysiologic mechanisms of multiple myeloma.

This study identified and characterized PKCβ as a therapeutic target in CLL, including CLL resistant to BTKis. Inhibition of PKCβ suppressed both BCR and Wnt/β-catenin signaling, delayed disease progression in vivo, overcame BTKi resistance mechanisms, and enhanced response to BCL-2 inhibition. See related commentary by Jebaraj and Stilgenbauer, p. 21.

Golcadomide is an oral cereblon-modulating agent for the treatment of DLBCL. It exhibited rapid, deep, and sustained degradation of IKZF1 and IKZF3, preferentially accumulated in lymphoma residence tissues, and delivered robust antitumor activity. These results provide a strong rationale for continued clinical investigation of golcadomide for patients with DLBCL.

Menin inhibitors have the potential to reshape treatment paradigms in acute leukemia. There are multiple promising preclinical combinations that require careful clinical trial design and implementation for a successful translation into the clinical setting.

In this issue of Blood Cancer Discovery, Newman and colleagues investigated the impact of genetic ancestry on molecular subtypes, genomic alterations, and survival outcomes in a diverse cohort of patients with T-cell acute lymphoblastic leukemia. They demonstrated that the prognostic utility of genomic alterations varied by ancestry, in particular, with NOTCH1 mutations having no prognostic utility in patients of predominantly African ancestry, and their findings highlight the importance of considering genetic ancestry in the risk stratification of patients with T-ALL. See related article by Newman et al., p. 412.

This study identifies RUNX1C as a contributor to AML chemoresistance and an inducer of quiescence through BTG2. Targeting RUNX1C with RNA-based approaches disrupts this state and improves chemotherapy response, highlighting RUNX1C inhibition as a promising strategy to overcome resistance and enhance treatment efficacy in AML.

We present a single-cell reference atlas of human hematopoiesis and a computational tool for rapid mapping and classification of healthy and leukemic cells. Applied to AML, this has enabled single-cell analysis at the scale of hundreds of patient samples, revealing the full breadth of derailment of differentiation in AML. See related commentary by Berger and Penter, p. 280.

This commentary explores the concept and utility of studying oncogene co-expression at single-cell resolution and its clinical and biological implications. We emphasize the importance of scalable methods, mathematically driven quantification models, and artificial intelligence integration to enhance the clinical utility of this approach.