# Targeted aberrant signaling in CBL-mutant leukemia

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2020 · $394,614

## Abstract

PROJECT SUMMARY
CBL mutations are common in chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML),
myelodysplastic syndrome, and clonal hematopoiesis of indeterminate potential (CHIP). CBL is an E3 ubiquitin
ligase that recognizes phosphorylated receptor tyrosine kinases (RTKs) and mediates both downstream
signaling and destruction of activated RTKs that are critical for leukemogenesis, including KIT, FLT3 and
CSF2RB. (1, 2) There are no therapies that specifically address CBL-mutant leukemia, an ideal target for
genotype-directed therapy. CBL is a central node for kinase signaling, and unlike most common mutations in
leukemia, CBL mutations result in a gain-of-function, activating specific signaling pathways. CBL-mediated
ubiquitination of activated tyrosine kinases triggers their proteasomal degradation, a negative feedback for
ongoing signaling. In leukemia, CBL mutations specifically abolish the ubiquitin ligase activity, leaving CBL-
mediated downstream signaling unchecked, resulting in prolonged kinase signaling and increased cellular
proliferation. The central goal of this proposal is to understand the mechanistic basis of CBL mutations in order
to identify the set of proteins and pathways that are dysregulated and can be targeted for the treatment of CBL-
mutant leukemia. In Aim 1, we will determine the specific phosphorylated proteins that are degraded by CBL in
leukemia cells and stabilized when CBL is mutated, leading to constitutive signaling. Mechanistically, we will
examine how specific point mutations in CBL alter the binding and ubiquitination of substrates, and the initiation
of downstream signaling. In Aim 2, we will investigate the combinations of kinase inhibitors with greatest
therapeutic potential using both in vitro and in vivo models. Preliminary studies highlight the aberrant activation
of LYN kinase and PI3K/AKT signaling pathways in cells with CBL RING domain mutations. We hypothesize
that inhibiting these signaling pathways, and other kinases identified in Aim 1, will selectively target CBL-mutant
cells and may have therapeutic activity in CBL-mutant myeloid malignancies. We will develop and characterize
in vivo models of CMML with Cbl mutations, and test the efficacy of FDA approved drugs, dasatinib and
dactolisib, alone and in combination. In Aim 3, we will investigate the biology of the CRL5CISH ubiquitin ligase.
Preliminary studies identified CRL5CISH ubiquitin ligase as a potential reserve for CBL, regulating an overlapping
set of signaling pathways, but also degrading key signaling molecules that are not degraded by CBL. We will
examine the biology of this CRL5CISH ubiquitin ligase in CBL wild-type and mutant cells. Manipulation of the
activity of this ubiquitin ligase could alter ubiquitination of substrates that are aberrantly regulated in CBL-mutant
leukemias. Overall, this project will elucidate the biology and therapeutic vulnerabilities in CBL-mutant leukemia.
The project will leverage the ex...

## Key facts

- **NIH application ID:** 9854835
- **Project number:** 2P01CA066996-21
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Benjamin Levine Ebert
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,614
- **Award type:** 2
- **Project period:** — → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854835

## Citation

> US National Institutes of Health, RePORTER application 9854835, Targeted aberrant signaling in CBL-mutant leukemia (2P01CA066996-21). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9854835. Licensed CC0.

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