This Blood Spotlight highlights the background and recent data surrounding the use of the recently approved interferon-γ neutralizing antibody emapalumab, Gamifant, for the treatment of hemophagocytic lymphohistiocytosis.

The cohesin complex plays an essential role in chromosome maintenance and transcriptional regulation. Recurrent somatic mutations in the cohesin complex are frequent genetic drivers in cancer, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of stromal antigen 2–mutant ( STAG2 -mutant) AML, we identified DNA damage repair and replication as genetic dependencies in cohesin-mutant cells. We demonstrated increased levels of DNA damage and sensitivity of cohesin-mutant cells to poly(ADP-ribose) polymerase (PARP) inhibition. We developed a mouse model of MDS in which Stag2 mutations arose as clonal secondary lesions in the background of clonal hematopoiesis driven by tet methylcytosine dioxygenase 2 ( Tet2 ) mutations and demonstrated selective depletion of cohesin-mutant cells with PARP inhibition in vivo. Finally, we demonstrated a shift from STAG2- to STAG1-containing cohesin complexes in cohesin-mutant cells, which was associated with longer DNA loop extrusion, more intermixing of chromatin compartments, and increased interaction with PARP and replication protein A complex. Our findings inform the biology and therapeutic opportunities for cohesin-mutant malignancies.

Deciphering the context-specific relationship between sequence and function is a major challenge in genomics. Existing tools for inducing locus-specific hypermutation and evolution in the native genome context are limited. Here we present a programmable platform for long-range, locus-specific hypermutation called helicase-assisted continuous editing (HACE). HACE leverages CRISPR-Cas9 to target a processive helicase-deaminase fusion that incurs mutations across large (>1000–base pair) genomic intervals. We applied HACE to identify mutations in mitogen-activated protein kinase kinase 1 (MEK1) that confer kinase inhibitor resistance, to dissect the impact of individual variants in splicing factor 3B subunit 1 (SF3B1)–dependent missplicing, and to evaluate noncoding variants in a stimulation-dependent immune enhancer of CD69. HACE provides a powerful tool for investigating coding and noncoding variants, uncovering combinatorial sequence-to-function relationships, and evolving new biological functions.

Macrophages exert antitumorigenic activity through phagocytosis, but phagocytosis-enhancing therapeutics have not improved acute myeloid leukemia (AML) outcomes. To identify phagocytosis regulators, we performed CRISPR knockout screens in human AML cells cocultured with human macrophages. We found that the “don’t eat me” signal CD47 inhibited mouse but not human macrophage phagocytosis. However, O-linked glycosylation and sialylation were strong negative regulators of phagocytosis. In AML, the cell surface mucin-like glycoprotein CD43 was the major effector of these pathways. Inhibition of phagocytosis by CD43 was dependent on the length of its ectodomain and independent of the macrophage sialic acid receptors SIGLEC-1, SIGLEC-7, and SIGLEC-9. The inhibitory effects of CD43 extended beyond human macrophages to natural killer and T cells. Thus, CD43 forms a glyco-immune barrier that restrains both innate and adaptive antileukemic immunity.

At the health systems level, lack of diagnostic ability, inadequate access to trained providers, and limited drug availability provide significant barriers to cancer care delivery. This article outlines an urgent call to action to improve access to precision oncology therapies in lower- and middle-income countries, drawing upon lessons from international efforts in oncology and infectious disease.

Programmable control of gene expression in specific cell types is essential for both basic discovery and therapeutic intervention, yet current strategies lack scalability across diverse cellular contexts. Here, we introduce SPICE (Splicing Proportions In Cell types), an integrated experimental and computational framework that harnesses alternative RNA splicing as a programmable modality for cell type-specific gene regulation. To power SPICE, we constructed a massively parallel reporter assay (MPRA) comprising 46,372 human-derived sequences and profiled exon skipping across 43 cell lines spanning 10 lineages, uncovering widespread cell type-specific exon skipping. Using this data, we trained deep learning models that both predict splicing in unseen contexts and generate synthetic sequences with programmed, cell type-specific splicing patterns. Leveraging these models, we further engineered sequences that selectively splice in cells harboring oncogenic splicing factor mutations, demonstrating translational potential. SPICE provides a generalizable strategy for dissecting splicing regulation and engineering alternative splicing as a gene expression regulatory layer for research and therapeutic applications. One Sentence Summary: We introduce SPICE, an integrated framework that couples large-scale splicing assays with generative design to uncover regulatory principles and design programmable, cell-specific gene expression for research and therapeutic applications.