# Characterizing the MSI2 network in leukemia

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $404,981

## Abstract

PROJECT SUMMARY/ABSTRACT
An evolutionary conserved developmental program is carefully maintained in hematopoietic stem cells (HSCs).
Genetic alterations and epigenetic mechanisms can alter the balance of normal blood development resulting in
hematological malignancies. Our laboratory and others have found that the MUSASHI2 (MSI2) RNA binding
proteins is highly expressed in the most aggressive cancers and predicts a poor clinical outcome in acute
myeloid leukemia (AML) patients. Genetic models have found that MSI2 is required for leukemia stem cell
function. Utilizing a new way to identify mRNA targets of RNA binding proteins, we have found that MSI2
activity is increased in leukemia stem cells compared to normal stem and progenitor cells. This surprising
finding suggests that RNA binding protein function can be dysregulated beyond just expression differences.
We hypothesize that the MSI family of RNA binding protein have differential activity in AML compared to
normal cells and that MSI enhances the dysregulated epigenome in AML. We propose two possible
mechanisms for this intriguing finding 1) MSI2 associated RBPs compete for MSI2-binding sites and 2) Post-
translation modifications can modulate MSI2 activity. Our preliminary data has uncovered that MSI2 can
mediate resistance to PRMT5 and that PRMT1 and PRMT5 can directly methylate MSI2. PRMT5 inhibitors are
being investigated as therapeutic targets and our proposal suggests a novel link to this pathway and may
explain cell context MSI2 activity. Our proposal will utilize new genetic models to characterize MSI2 targets in
specific cellular contexts and explore the MSI2 associated program to identify new therapeutic strategies in
AML.

## Key facts

- **NIH application ID:** 10318669
- **Project number:** 5R01CA193842-07
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Michael Kharas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $404,981
- **Award type:** 5
- **Project period:** 2015-04-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318669

## Citation

> US National Institutes of Health, RePORTER application 10318669, Characterizing the MSI2 network in leukemia (5R01CA193842-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10318669. Licensed CC0.

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