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A noncoding mutation in the NOTCH1 gene initiates oncogenic NOTCH signaling via wild-type NICD stabilization in CLL
Min Guo1, Tugba Memis1, Alena Sophie Ehrmann2,3
1Department of Internal Medicine I, University Hospital Ulm, Ulm, Germany.
Abstract:
Chronic lymphocytic leukemia (CLL) is the most common chronic blood cancer in adults. Active NOTCH signaling in CLL is associated with poorer prognosis. Importantly, patients with CLL with NOTCH1 noncoding mutations in the 3' untranslated region (3'UTR) manifested with a more aggressive disease course even compared with those with mutations in the NOTCH1 coding region. Here, we comprehensively characterize a cryptic splice acceptor site in the 3'UTR of the NOTCH1 gene being converted into a stronger site. The functional consequences of the resulting NOTCH1 protein variants depend on the exact localization of the splice site, the used open reading frame, and the appearance of the next stop codon. The most frequent 3'UTR mutation (g.139390152, A>G) generates a novel NOTCH1 protein, lacking the PEST domain but expressing an altered C terminus consisting of 68 amino acids. Mechanistically, we demonstrate that this splice variant (NOTCH1 152) is transcriptionally less active and dysregulates the regular ubiquitination-dependent degradation of the wild-type NICD (NOTCH1 intracellular domain) in trans. Thus, the NOTCH1 152 variant acts as a "sponge" protein in a novel mechanism of oncogenic NOTCH signaling activation, explaining the detrimental disease outcome of patients with CLL with noncoding NOTCH1 mutations. We propose that the detection of NOTCH1 152 protein by specific antibodies is a useful prognostic marker for patients with CLL.
Insights
A novel NOTCH1 splice variant (NOTCH1 152) in Chronic Lymphocytic Leukemia (CLL) acts as a "sponge" protein, driving aggressive disease. Detecting this variant offers a new prognostic marker for CLL patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Chronic Lymphocytic Leukemia (CLL) is the most prevalent chronic blood cancer in adults.
- Elevated NOTCH signaling correlates with poorer prognosis in CLL.
- Non-coding NOTCH1 mutations, particularly in the 3' untranslated region (3'UTR), are linked to more aggressive disease compared to coding region mutations.
Purpose of the Study:
- To characterize a cryptic splice acceptor site in the NOTCH1 3'UTR that becomes activated by mutation.
- To elucidate the functional consequences of novel NOTCH1 protein variants arising from 3'UTR mutations.
- To investigate the mechanism by which these variants contribute to oncogenic NOTCH signaling activation in CLL.
Main Methods:
- Comprehensive characterization of a cryptic splice acceptor site in the NOTCH1 3'UTR.
- Functional analysis of NOTCH1 protein variants, including the frequent g.139390152 (A>G) mutation.
- Investigation of the variant's effect on NOTCH1 protein stability, transcriptional activity, and ubiquitination-dependent degradation.
Main Results:
- A frequent 3'UTR mutation (g.139390152, A>G) creates a novel splice variant (NOTCH1 152) lacking the PEST domain and possessing an altered C-terminus.
- NOTCH1 152 is transcriptionally less active but dysregulates the degradation of wild-type NOTCH1 intracellular domain (NICD) in trans.
- This variant functions as a 'sponge' protein, leading to oncogenic NOTCH signaling activation.
Conclusions:
- The NOTCH1 152 splice variant represents a novel mechanism for activating oncogenic NOTCH signaling in CLL.
- This mechanism explains the aggressive disease course observed in CLL patients with non-coding NOTCH1 mutations.
- Detection of NOTCH1 152 protein using specific antibodies may serve as a valuable prognostic marker for CLL.
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