Correlation Engine 2.0
Clear Search sequence regions


  • cancer (1)
  • cellular (1)
  • expressed genes (1)
  • factor (5)
  • function (3)
  • humans (1)
  • leukemia (1)
  • neutrophils (1)
  • NGF (1)
  • phenotypes (1)
  • protein human (1)
  • rna (1)
  • RUNX1 (4)
  • Sizes of these terms reflect their relevance to your search.

    Single-gene missense mutations remain challenging to interpret. Here, we deploy scalable functional screening by sequencing (SEUSS), a Perturb-seq method, to generate mutations at protein interfaces of RUNX1 and quantify their effect on activities of downstream cellular programs. We evaluate single-cell RNA profiles of 115 mutations in myelogenous leukemia cells and categorize them into three functionally distinct groups, wild-type (WT)-like, loss-of-function (LoF)-like, and hypomorphic, that we validate in orthogonal assays. LoF-like variants dominate the DNA-binding site and are recurrent in cancer; however, recurrence alone does not predict functional impact. Hypomorphic variants share characteristics with LoF-like but favor protein interactions, promoting gene expression indicative of nerve growth factor (NGF) response and cytokine recruitment of neutrophils. Accessible DNA near differentially expressed genes frequently contains RUNX1-binding motifs. Finally, we reclassify 16 variants of uncertain significance and train a classifier to predict 103 more. Our work demonstrates the potential of targeting protein interactions to better define the landscape of phenotypes reachable by missense mutations. Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

    Citation

    Kivilcim Ozturk, Rebecca Panwala, Jeanna Sheen, Kyle Ford, Nathan Jayne, Andrew Portell, Dong-Er Zhang, Stephan Hutter, Torsten Haferlach, Trey Ideker, Prashant Mali, Hannah Carter. Interface-guided phenotyping of coding variants in the transcription factor RUNX1. Cell reports. 2024 Jul 23;43(7):114436

    Expand section icon Mesh Tags

    Expand section icon Substances


    PMID: 38968069

    View Full Text