# Function of Musashi-2 Methylation in Normal and Malignant Hematopoiesis

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $46,752

## Abstract

Project Abstract
 Acute myeloid leukemia (AML) is an aggressive, heterogeneous disease and is
characterized by the expansion of immature myeloid progenitors and the inhibition of myeloid
differentiation. AML arises when the complex process of blood formation, known as
hematopoiesis, goes wrong. While progress has been made to develop new treatments and
therapies for AML, little progress has been made in the past decades. The Musashi (MSI) family
of proteins, MSI1 and MSI2 are RNA-binding proteins (RBPs) and are responsible for post-
transcriptional regulation of genes in stem cell compartments. However, MSI2 plays a prevailing
role to MSI1 in the blood. Here, MSI2 maintains hematopoietic stem cells (HSCs) and determines
lineage bias. MSI2 has been implicated in a variety of solid tumors and leukemias suggesting
targeting it could be a beneficial cancer therapy. Previous studies demonstrate MSI2 expression
is a negative prognostic marker for AML and myelodysplastic syndromes (MDS) as upregulation
of MSI2 correlates with poor prognosis and worse clinical outcomes for patients. MSI2 cooperates
with the fusion protein BCR-ABL1 during leukemogenesis, potentiating HSC transformation in the
presence of other mutations. MSI2 is also able to sustain the mixed-lineage leukemia (MLL) stem
cell regulatory program through interaction with Hoxa9, Myc, and Ikzf2 mRNAs. Deletion of MSI2
decreases LSC survival and delays leukemia initiation and progression in vivo. Many studies
demonstrate the variety of responsibilities MSI2 has in regulating translation in HSCs and
leukemic stem cells, but there remains a significant gap in knowledge as to how MSI2 function is
regulated. The proposed project aims will define how MSI2 function changes when different post-
translational modifications are added. Our preliminary data establishes protein arginine
methyltransferases (PRMT) 1 and 5 can methylate MSI2, and in a genome wide CRISPR screen,
MSI2 was the top driver of resistance to PRMT5 inhibition. The outlined proposal will expand our
understanding of MSI2 function in normal and malignant stem cell regulatory programs to inform
design of novel therapeutic strategies to treat AML.

## Key facts

- **NIH application ID:** 10449093
- **Project number:** 5F31CA257204-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Chiara Maria Evans
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2021-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10449093

## Citation

> US National Institutes of Health, RePORTER application 10449093, Function of Musashi-2 Methylation in Normal and Malignant Hematopoiesis (5F31CA257204-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10449093. Licensed CC0.

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