Biology subjects

Leach, B.

Publications and source records attributed to Leach, B..

2 recordsLinked to original sources

bioRxiv2025

The MLLT3 YEATS domain is a dual reader of histone marks (H3K9/18/27ac/cr) and ncRNA (7SK), linking epigenetic and RNA signaling to regulate hematopoiesis

The protein MLLT3 (AF9) is a critical regulator of hematopoiesis. The N-terminal YEATS domain of MLLT3 is an epigenetic reader that binds to acetylated as well as crotonylated lysine. Using PAR-CLIP, biochemical assays, and NMR based mapping of binding, we demonstrate that the YEATS domain of MLLT3 binds to a specific stem-loop region of the noncoding RNA 7SK. 7SK is a noncoding RNA with a well-documented function in transcriptional elongation. We developed point mutations in the YEATS domain that disrupt RNA binding while having no effect on binding of acetylated histone peptides to probe the specific role of RNA binding in MLLT3 function. Our results show loss of RNA binding by MLLT3 skews hematopoietic differentiation away from the myeloid lineage and toward the lymphoid lineage and has substantial effects on gene expression, confirming the essential nature of MLLT3-RNA binding for function.

biochemistry↗

bioRxiv2025

A potent and selective TNKS2 inhibitor for tumor-selective WNT suppression

Hyperactive WNT signaling is a potent cancer driver, but clinical translation of WNT inhibitors has been hampered by on-target toxicities. WNT signaling can be constrained through inhibition of the PARP family enzymes Tankyrase 1 (TNKS1) and Tankyrase 2 (TNKS2), however, existing TNKS inhibitors suppress WNT signaling in both tumor and healthy tissues. In this study, we show that the loss of chromosome 8p that occurs in approximately half of advanced epithelial malignancies, creates a collateral vulnerability that enables tumor-selective inhibition of Tankyrase activity. 8p loss depletes expression of TNKS1 and creates a tumor-specific dependency on the functionally redundant TNKS2 protein. Through structure-guided drug design, we identify a first-in-class TNKS2-selective inhibitor that can drive selective WNT inhibition in TNKS1-deficient oncogenic cell and organoid models. This work demonstrates a targetable vulnerability in multiple cancer types, providing a new approach to potent and selective WNT-targeted therapies.

cancer biology↗