# Elucidation of the molecular mechanisms of the RBM15-MKL1 fusion protein in acute megakaryoblastic leukemia

> **NIH NIH F31** · YALE UNIVERSITY · 2024 · $51,474

## Abstract

PROJECT SUMMARY/ABSTRACT
Acute megakaryoblastic leukemia (AMKL) is a form of cancer most prevalent in children under four years old.
Targeted AMKL-specific treatment options are limited, and survival rates remain variable. A major obstacle to
improving therapy options for AMKL is the dearth of data regarding the mechanisms that contribute to AMKL
leukemogenesis. Of several known causative genomic alterations in AMKL, the t(1;22) translocation, which
encodes the RBM15-MKL1 (RM) fusion protein, is considered a neonatal mutation as it is always diagnosed in
children younger than 6 months old. RNA-binding motif protein 15 (RBM15) is required for recruitment to RNA
of the N6-methyladenosine (m6A) writer complex and subsequent epitranscriptomic modification of the
transcripts. Megakaryoblastic leukemia 1 (MKL1) is a transcriptional coactivator and is involved in gene
expression and megakaryocyte maturation. RM retains all functional domains of both proteins and, despite our
understanding of these proteins, the properties of RM itself remain poorly understood. The goal of this proposal
is to investigate the molecular mechanisms by which RBM15’s association with RNA in the context of the RM
fusion protein contributes to leukemogenesis. Based on our preliminary data, we hypothesize that RM alters
gene expression via binding to RNA and promoting modification of the epitranscriptome which promotes
oncogenesis via aberrant Wnt signalling. To test this hypothesis, two Aims are proposed. The first Aim is to
identify RNAs bound and m6A modified by RM using enhanced crosslinking and immunoprecipitation
sequencing techniques. This will determine which transcripts are targeted by RM and which adenosine residues
are modified following RM binding, and functional analysis will determine pathways important to leukemogenesis.
Computational integration with RNA-seq will provide insight into the fate of RNAs targeted by the RM fusion
protein in contrast to control RBM15. The second Aim is to investigate the role of candidate proteins in RM-
mediated leukemogenesis by knocking down select candidates in a physiologically relevant murine
megakaryoblastic cell line model. In vitro and in vivo assessment of leukemogenesis will determine the
requirement of these candidates for the survival of leukemia cells in vitro and for maintenance of disease in vivo.
These experiments will provide insight into the transcriptomic and epitranscriptomic effects of RM that are critical
to the mechanistic function of the fusion protein. A better understanding of the mechanisms driving RM-mediated
AMKL will significantly broaden knowledge of AMKL leukemogenesis and provide potential novel therapeutic
avenues to improve outcomes and survival rates of neonates with this disease.

## Key facts

- **NIH application ID:** 10832979
- **Project number:** 5F31CA271571-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Madeline Young Mayday
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $51,474
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10832979

## Citation

> US National Institutes of Health, RePORTER application 10832979, Elucidation of the molecular mechanisms of the RBM15-MKL1 fusion protein in acute megakaryoblastic leukemia (5F31CA271571-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10832979. Licensed CC0.

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