# MYB family alterations in pediatric gliomas

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2021 · $554,504

## Abstract

ABSTRACT
Pediatric low-grade astrocytomas (PLGAs) as a group are the most common solid tumor in children. While
rarely fatal, patients frequently experience a relapsing/remitting course wherein repeated cycles of
chemotherapy or radiation are required to contain the disease, often inducing irreparable neurologic damage.
Therefore, less toxic therapies are urgently needed. We and others have identified genetic drivers of PLGAs in
order to develop more specific and effective targeted therapeutic strategies. This proposal addresses the
second most common set of alterations in PLGAs, those involving MYB transcription factors (TFs). In recent
studies we identified rearrangements involving MYB and MYBL1 in 10% of PLGAs. Each rearrangement is
associated with distinct PLGA subtypes. Angiocentric gliomas harbor fusions between a truncated MYB and a
truncated portion of the tumor suppressor and myelination gene, QKI. A second tumor subtype, diffuse
astrocytoma, frequently exhibits MYBL1 truncation as the only oncogenic change. Similar genetic
rearrangements of MYB/MYBL1 have now been implicated in leukemias and adenoid cystic carcinomas. While
rearrangements in MYB/MYBL1 are common driver events in PLGAs the biological consequences of these
oncogenic changes are not understood. To develop new therapeutic approaches we will determine how the
distinct mutant MYB transcription factors contribute to oncogenesis, and whether altered QKI function is critical
for growth of angiocentric gliomas. We will address the biology of MYB/MYBL1 oncogenes and implications for
new therapies in the following Specific Aims: Aim 1: Test the hypothesis that MYB and MYBL1 alterations
contribute to tumorigenesis via distinct but related mechanisms using ChIP-Seq and RNA-Seq to define
transcription factor and signaling networks activated by MYB genes. Aim 2: Test the hypothesis that the MYB
fusion partner QKI contributes to tumorigenesis by altering RNA processing. We will determine whether MYB-
QKI retains RNA binding ability and thereby alters RNA splicing. Aim 3: Identify MYB activated genes
functionally critical for tumor growth and amenable to targeting with small molecule therapeutics. This will be
done by evaluating novel therapeutics to target MYB/MYBL1 protein regulation and using a CRISPR-screen to
identify key gene dependencies for MYB-induced tumors. These studies will provide basic biological insights
into the function of MYB proteins and QKI in pediatric astrocytomas and other cancers with MYB alterations.
This knowledge will directly inform the development of new rational therapeutics for pediatric astrocytomas and
other cancers with MYB transcription factor alterations.

## Key facts

- **NIH application ID:** 10119253
- **Project number:** 5R01CA215489-05
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** RAMEEN BEROUKHIM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $554,504
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119253

## Citation

> US National Institutes of Health, RePORTER application 10119253, MYB family alterations in pediatric gliomas (5R01CA215489-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10119253. Licensed CC0.

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