ASH 2025

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Using the combination of Tempus Lens data as well as pre-clinical experiments, this project investigates the role of the ARID1A subunit of the SWI/SNF chromatin remodeling complex in acute myeloid leukemia (AML) leukemogenesis. Using Tempus Lens, 592 patients with AML who had both DNA (Tempus xT) and RNA (Tempus xR) sequencing were identified. The study found that low ARID1A gene expression was significantly associated with improved real-world overall survival compared to ARID1A high expression. This finding remained robust even after adjusting for other BAF complex genes. Furthermore, the ARID1A-high group showed significant enrichment of recurrent mutations in FLT3, NPM1, and NRAS. Functional mouse model studies confirmed that ARID1A deletion impairs AML cell survival by reducing proliferation, drastically decreasing clonogenic ability, and inducing differentiation and death. The severity of ARID1A loss was comparable to inhibiting the common ATPase subunit. These results suggest that targeting ARID1A may offer similar therapeutic efficacy to ATPase inhibition, but with a potentially narrower target range and reduced toxicity.

This study demonstrates that whole genome sequencing (WGS) can identify BCR::ABL1 fusion events and uncover novel breakpoints and variants of clinical significance, particularly when used in conjunction with RNA-sequencing for profiling hematological malignancies. While traditional methods for detecting the BCR::ABL1 fusion gene in leukemias like chronic myeloid leukemia are often limited, WGS has the ability to detect a wide array of genetic changes, including atypical fusion variants. Retrospectively analyzing 215 clinical samples sent for testing at Tempus, which received both WGS via Tempus xH* and RNA-seq via Tempus xR, the study identified BCR::ABL1 fusions in 29 samples and uncovered two abnormal breakpoints with clinical implications. Furthermore, WGS data was used to identify the presence of pathogenic or likely pathogenic mutations in ASXL1 and RUNX1, both of which may impact survival and treatment outcomes. These findings suggest WGS is a powerful tool for the comprehensive genomic profiling of leukemia, with potential implications for personalized medicine.