Highlighted Research Articles

Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with increased risk of several chronic diseases. However, gene-specific CHIP implications remain to be characterized. Usui and colleagues conducted an epidemiologic evaluation of 140,597 individuals in BioBank Japan, including 1,157 cases with CHIP in TP53 gene (TP53-CHIP) identified by high-coverage sequence data. In this largest-to-date cohort followed over a decade, TP53-CHIP associated with myeloid and lymphoid neoplasms, and respiratory disease mortality. The impact of TP53-CHIP was modulated by an interplay of host and environmental factors. For example, alcohol consumption in TP53-CHIP carriers conferred higher risk of liver disease only in the presence of a genetic variant in an alcohol-metabolizing enzyme. These findings elucidate TP53-CHIP’s role in disease pathogenesis and its potential to inform personalized risk management.See article, p. 298.The differentiation landscape of an acute myeloid leukemia (AML) patient reflects key biological properties about their disease, including identity of the transforming cell and the differentiation blocks incurred by their genetic driver alterations. To capture the breadth of aberrant differentiation patterns in AML, >1 million single-cell transcriptomes from 318 patient samples were compared to 55 distinct cellular states uncovered from analysis of more than 260,000 single-cell transcriptomes of normal bone marrow. This revealed 12 recurrent patterns of aberrant differentiation in AML, indicating phenotypic convergence across genetically diverse samples. These refined leukemic cell state definitions provide a means for improving AML classification and targeted therapy development.See article, p. 307.As disease subtyping forms a framework for prognosis, refining the classification of disease subtypes paves the way for more precise treatments. Current classification of Burkitt lymphoma (BL) is based on clinical and genetic parameters. In this study, Thomas and colleagues describe the disease at the level of DNA methylation patterns, or epitypes. Using a well-annotated set of data from a large retrospective cohort, they show that samples grouped by the abundance of methylation marks are associated with distinct clinical outcomes. If validated in additional cohorts and integrated into the current clinical standards, the findings could offer increased precision of risk assessment for BL patients.See article, p. 325.Positioning of active enhancers near proto-oncogenes through genomic rearrangement can result in oncogene activation. A systematic discovery of these enhancer hijacking events in 39 complex karyotype acute myeloid leukemia (ckAML) patient samples using a novel computational tool, Pyjacker, identified MNX1 activation in ckAML. MNX1 was shown to be an oncogene in AML, activated in 1.4% of AML patients, and was observed to be a consequence of an enhancer hijacking event mediated by deletion 7q, which brings a CDK6 enhancer into the vicinity of MNX1. Identification of additional enhancer hijacking events highlights Pyjacker as an accurate tool of broad applicability.See article, p. 343.The B-cell receptor (BCR) consists of immunoglobulin light (IGL) and heavy (IGH) chains and CD79A/B signaling subunits. BCR signaling is vital for B cells, including malignant lymphoma, a dependency exploited by polatuzumab, a first-line therapy targeting CD79B. Here, Varano and colleagues show that high-grade B cell lymphomas with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) are often hyporesponsive to polatuzumab due to absence of surface BCR. Elucidating the underlying biology, the authors show that BCR silencing reactivates RAG recombinases, triggering MYC translocations into IGL loci. Even more surprisingly, HGBCL-DH-BCL2 remain dependent on intracellular IGH protein.See article, p. 364.