# Elucidating Oncogenic Mechanisms of CBL RING Domain Mutations

> **NIH NIH F30** · HARVARD MEDICAL SCHOOL · 2021 · $51,036

## Abstract

PROJECT SUMMARY/ABSTRACT
CBL is an E3 ubiquitin ligase that plays an essential role in both the positive and negative regulation of tyrosine
kinases and the downstream signaling cascades that drive myeloid proliferation and differentiation. Recurrent
mutations in CBL have been identified in a number of myeloid malignancies, including juvenile and chronic
myelomonocytic leukemia (JMML and CMML, respectively), and analysis of the distribution of the mutations
within CBL has revealed that these mutations cluster in the RING domain responsible for its E3 ubiquitin ligase
catalytic function. It has been hypothesized that these mutations lead to a loss of negative regulation of signal
transduction, while the maintenance of CBL scaffolding function preserves positive regulation of signaling.
Dysregulation of receptor tyrosine kinase (RTK) and non-receptor tyrosine kinase (nRTK) signaling by CBL
mutations can promote leukemogenesis by disrupting the natural regulation of cell growth and differentiation.
While the function of CBL mutations have been studied in the regulation of specific RTKs, nRTKs, and
downstream signaling pathways, a comprehensive analysis of CBL function and the consequences of CBL
RING domain mutations has not been executed. Most importantly, targeted therapies for CBL-mutated myeloid
malignancies have not been developed. Preliminary phospho-proteomic experiments have shown the
hyperactivation of Pi3k/Akt/mTor signaling in CBL-mutant cells. Here, I propose a series of experiments to 1)
identify dysregulated signaling pathways and key protein-protein interactions in CBL RING domain mutant cells
using IP-MS, 2) explore the effect of small molecule inhibition and genetic perturbation of Lyn and the
Pi3k/Akt/mTor signaling pathway on cytokine hypersensitivity and hyperactivation of signaling in vitro. The
proposed studies will be the first comprehensive analysis of mutant CBL function and will provide insight into
therapeutic vulnerabilities in CBL-mutated myeloid malignancies.

## Key facts

- **NIH application ID:** 10098306
- **Project number:** 5F30CA236112-03
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Sebastian Hassan John Koochaki
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10098306

## Citation

> US National Institutes of Health, RePORTER application 10098306, Elucidating Oncogenic Mechanisms of CBL RING Domain Mutations (5F30CA236112-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10098306. Licensed CC0.

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