# Integrative Analyses of Saturation CRISPR Protein Scan

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $132,000

## Abstract

PROJECT SUMMARY/ABSTRACT
 Epigenetic mechanisms play a critical role in controlling gene expression during normal development and are
often altered in disease states, particularly in cancer. MLL-rearranged (MLL-r) leukemias account for 5-10%
of human acute leukemia and is associated with poor prognosis. The unmet clinical needs and the lack of
effective targeted therapy to the MLL-r leukemias emphasize the need for novel regimens. Recent cancer
epigenetics studies discovered a central role for the histone H3 lysine 79 (H3K79) methyltransferase
DOT1L in MLL-r leukemogenesis. Important clinical responses have been noted with DOT1L inhibitor
treatment as a single agent, however, it is expected that combination treatments will be necessary.
 Our preliminary studies proposed in the parent award R01 CA236626 based on a high-density CRISPR
genetic screen of DOT1L have identified the potential of “saturation CRISPR protein scan” in de novo
functional domain discovery. The objective of this Revision Application is to establish a computational pipeline
to facilitate the data analyses of the saturation CRISPR protein scan. Our central hypothesis is that saturation
CRISPR protein scan data harbor clinically impactful information that can be further explored through adaptation
of the integrative informatics tools from the ITCR Program. We will (Aim 1) integrate the saturation CRISPR
protein scan with cBioPortal (an integrative clinical genomic database; funded by ITCR) to identify clinically
relevant alleles, and (Aim 2) streamline the saturation CRISPR protein scan with DINC 2.0 (a parallelized meta-
docking method for the incremental docking of large ligands; funded by ITCR) to identify lead epigenetic ligands
to the CRISPR defined hotspots.
 This study is innovative because (1) it introduces a novel concept of using saturation CRISPR genetic
screens for epigenetic ligand discovery, and (2) it establishes an analysis pipeline for a novel field that
bridges the functional genomics, protein domain identification, and therapeutics discovery.
 The impact of this research will be of significance because (1) it immediately provides novel therapeutic
opportunities against the difficult-to-treat MLL-r leukemias, and (2) the computational pipeline established
in this proposal and streamlined with the ITCR supported integrative informatics tools will help identify novel
functional elements for future pharmaceutical targeting in multiple types of cancers.

## Key facts

- **NIH application ID:** 10058930
- **Project number:** 3R01CA236626-02S1
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Chun-Wei David Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $132,000
- **Award type:** 3
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058930

## Citation

> US National Institutes of Health, RePORTER application 10058930, Integrative Analyses of Saturation CRISPR Protein Scan (3R01CA236626-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10058930. Licensed CC0.

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