# The role, mechanism, and therapeutic potential of METTL1 in acute myeloid leukemia

> **NIH NIH R37** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2024 · $443,220

## Abstract

PROJECT SUMMARY:
Acute myeloid leukemia (AML) is a devastating hematopoietic malignancy characterized by clonal expansion of
leukemia stem cells (LSCs). Despite advancements in chemotherapy regimens and targeted therapies, most
AML patients remain incurable. Thus, novel therapies targeting key leukemogenic pathways are needed. RNA
modifications are essential modulators of post-transcriptional gene regulation, and their dysregulation emerges
as a contributor to AML. Through an integrated analysis of genome-wide CRISPR/Cas9 screen data, we
discovered that AML cells preferentially depend on METTL1, an RNA methyltransferase that mainly catalyzes
7-methylguanosine (m7G) modification on transfer RNAs (tRNAs). METTL1 is highly expressed in LSCs and
AML specimens, and its high expression is associated with poor clinical outcomes. METTL1 depletion
significantly suppresses AML growth, eradicates LSCs in vitro, and attenuates AML progression in an AML
patient-derived xenograft (PDX) model. Importantly, those effects are largely dependent on METTL1’s m7G
methyltransferase activity, offering a unique opportunity for AML therapy through the development of small-
molecule inhibitors targeting its enzymatic activity. Via a high-throughput screen, we have discovered a selective
and potent METTL1 inhibitor with promising anti-AML activity. Moreover, METTL1 loss significantly reduces the
m7G abundance on tRNAPheGAA and its overall expression. This, in turn, leads to translation suppression of
transcripts that heavily rely on tRNAPheGAA-related codons, such as tyrosine-protein kinase HCK. The decreased
expression of HCK due to METTL1 depletion could further disrupt C-X-C chemokine receptor 4 (CXCR4)
signaling, which is essential for LSC homeostasis. Despite these insights, we do not yet understand the exact
mechanisms by which METTL1 loss results in AML suppression and LSC eradication. We hypothesize that
METTL1 functions as an m7G methyltransferase to drive AML development and sustain LSC frequency, making
it a potential ‘druggable’ target for treating high-risk AML. These hypotheses will be addressed in three Specific
Aims. Aim 1 will further consolidate the importance of METTL1 function in AML using mouse models. In this
Aim, we will utilize a number of AML models with different genetic backgrounds to rigorously determine the roles
of METTL1 in AML initiation and progression. Aim 2 will understand the role of METTL1/tRNAPheGAA/HCK
signaling in LSC homeostasis. This Aim will delineate the molecular mechanism through which the METTL1/m7G
axis facilitates LSC homing and self-renewal ability. Aim 3 will evaluate the therapeutic potential of
pharmacologically targeting METTL1 to treat AMLs.

## Key facts

- **NIH application ID:** 10943500
- **Project number:** 1R37CA292678-01
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** RUI SU
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $443,220
- **Award type:** 1
- **Project period:** 2024-06-14 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10943500

## Citation

> US National Institutes of Health, RePORTER application 10943500, The role, mechanism, and therapeutic potential of METTL1 in acute myeloid leukemia (1R37CA292678-01). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10943500. Licensed CC0.

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