# Mutations of Chromatin and its Modifying Machineries in Malignancies

> **NIH NIH R35** · NORTHWESTERN UNIVERSITY · 2023 · $927,430

## Abstract

Project Summary
Collective studies from my laboratory have focused on the molecular characterization of the function(s) and
biochemical properties of the epigenetic modifiers and the mutations that are associated with human cancer.
Our goal has been to determine how the mutations in these factors molecularly change the pattern of gene
expression resulting in cellular hyperproliferation and use these molecular pathways to identify targeted
therapeutics for cancer. Our detailed structural studies supported during the past seven years by this grant
R35CA197569 have allowed us to identify the atomic structure of Set1/COMPASS, and based on this
information, we have generated inhibitors towards its activity that are now being developed in our laboratory as
a tool compound to regulate COMPASS's function in cells for the ultimate use in clinic. On other fronts, our
analyses of the role of MLL3/COMPASS identified its interactions with the histone deubiquitinating enzyme
BAP1, providing a central epigenetic balance at enhancers and the regulation of gene expression in cancer
caused as the result of MLL3 mutations. Based on this information, we have a clinical trial at Northwestern
Medicine investigating the epigenetic role of this balance in cancer therapy. We have also generated BAP1
inhibitors that can regulate hyperactivated BAP1 function in cancers caused as the result of ASXL1 mutations
and such BAP1 inhibitors are being further investigated in our laboratory as biochemical and clinical tools. Our
detailed analysis of the role of histone H3K27M mutations in diffuse intrinsic pontine gliomas (DIPG) resulted in
the identification of a role for BET-domain containing factors such as Brd2 and Brd4 in DIPG pathogenesis. We
are collaborating with colleagues at Lurie Children's Hospital of Chicago to test these findings in clinic. These
studies also resulted in the identification of CATACOMB as an endogenous factor mimicking H3K27M and
regulating PRC2 function. As will be described in the application, other studies in the laboratory have probed
the mechanistic properties of diverse epigenetic factors in developmental regulation and in cancer. Additionally,
recent cataloging of somatic mutations in cancer and during natural aging has identified a large number of
mutations in the components of the MLL1-4, UTX, Set1A/B, and other epigenetic factors. Given that we have
developed a fantastic set of reagents and tools over the past twenty years in our laboratory towards these factors,
their associated proteins, chromatin, and other chromatin modifiers in multiple model systems, my laboratory is
in a very unique and strong position to define the molecular bases of these factors’ involvement in cancer
pathogenesis, and thus, for the purpose of targeted therapeutics. The goals of this R35 renewal application
are the continuation of our full molecular and biochemical characterization of the trithorax COMPASS
family and BAP1 complexes in the regulation of developmental ...

## Key facts

- **NIH application ID:** 10705758
- **Project number:** 5R35CA197569-09
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Ali Shilatifard
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $927,430
- **Award type:** 5
- **Project period:** 2015-08-13 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705758

## Citation

> US National Institutes of Health, RePORTER application 10705758, Mutations of Chromatin and its Modifying Machineries in Malignancies (5R35CA197569-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10705758. Licensed CC0.

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