{"doi":"10.1038/s41375-024-02429-x","title":"Non canonical c-CBL mutations define a specific phenotype of myeloid neoplasia","abstract":"CBL proteins are a family of RING finger E3 ubiquitin ligases that regulate proliferative signals via ubiquitination and degradation of tyrosine-phosphorylated signaling proteins, such as KIT, CSF-1, FLT3 and PDGF [ 1 ]. We previously described c-CBL RING finger mutations in myeloid neoplasia (MN), chiefly myelodysplastic/myeloproliferative (MDS/MPN) syndromes such as chronic myelomonocytic leukemia [ 2 , 3 ] and juvenile myelomonocytic leukemia [ 4 ]. c-CBL mutations are mainly heterozygous, but in some instances homozygous configuration can be found due to somatic uniparental disomy (UPD) affecting 11q chromosome [ 3 ]. Canonical c-CBL hits [missense (MS) mutations affecting linker and zinc finger domains] impair the ubiquitination function while preserving PI3K/AKT activation, common to RAS pathway, via LYN and KYN-mediated phosphorylation of c-CBL Y700, Y731, Y774. Somatic c-CBL hits have been linked to monocytosis and MPN phenotype [ 5 ] and, across MDS and acute myeloid leukemia (AML) phenotypes, these hits cluster with other RAS pathway gene mutations in unsupervised molecular clustering schemes [ 6 , 7 ]. Furthermore, outcome studies and prognostic scoring systems assigned a negligible prognostic role to c-CBL mutations in MDS [ 8 ] and AML [ 9 ], albeit without differentiating the type or mutational configuration. In addition to canonical mutations, c-CBL truncations can be also encountered and, since these lesions could impair not only the ubiquitin-association function, but also the PI3K/AKT activation function (enhanced through MS mutations), we hypothesized that these hits could lead to different, possibly less aggressive clinical phenotypes. To test our theory, we identified several cases of canonical (pathogenic MS mutations occurring in the linker region/zinc finger domains) and truncating c-CBL mutations taking advantage of a large genotyped and clinically annotated cohort (n = 11,543: 7211 AML, 3448 MDS, 575 MPN/MDS; 309 MPN) (Fig. 1A, B , Supplementary Table 1 ). Clonal hierarchy of c-CBL mutations was assessed using the previously established variant allele frequency (VAF)-based algorithm [ 10 ]. Pathogenicity of the variants was assessed according to in-silico predictions tools and literature evidence allowing for classification into evidentiary tiers [ 11 ]. All the analyses were performed with tier 1 and 2 hits but, to prove our point, truncating [not in-frame indel, nonsense, splice-site; (T)] and frameshift (FS) mutations not previously described (19 variants) were considered as tier 2 and thus, were included as well (Fig. 1C ). Fig. 1: Characteristics of our cohort of c-CBL mutated patients. A Flowchart of the study design and population selection. B Mutations distribution across the protein structure. Blue dots refer to missense mutations (MS), red dots to frameshift mutations (FS), yellow dots to truncating (T) (not in-frame indel, nonsense and splice-site) mutations. Underlined are the mutations further included in the analysis based on their pathogenicity. C Mutations selection. Mutations were divided according to their pathogenicity, functions (presumed from functional studies), and disease phenotype. We originally identified 322 mutations in 296 patients. Of these, the precise configuration was available in 261 cases (identified in 234 patients). According to our flow-chart, we selected, among MS variants, only tier 1–2 mutations occurring in linker region/zinc finger domains, and among T/FS variants, tier 1–2 mutations or mutations not previously described or with undefined pathogenicity, for a total of 203 variants in 184 patients: 147 harboring MS, 42 T/FS; 5 harboring both the type of mutation. More specifically, we included in MS cohort, 160 tier 1–2 mutations occurring in linker region/zinc finger domains (6 co-occurring with T/FS mutations) and in 21 T/FS tier 1–2 variants (2 co-occurring with canonical mutations) and 22 mutations without pathogenicity prediction (3 co-occurring with MS m","journal":"Leukemia","year":2025,"id":530864,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.964,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":567512,"name":"Carmelo Gurnari","orcid":"0000-0001-6829-5544","position":1,"is_corresponding":false},{"id":920584,"name":"Carlos Bravo‐Pérez","orcid":"0000-0001-9794-7847","position":2,"is_corresponding":false},{"id":261746,"name":"Arda Durmaz","orcid":"0000-0001-8394-600X","position":3,"is_corresponding":false},{"id":1410807,"name":"Nakisha D Williams","orcid":"0000-0001-8279-6476","position":4,"is_corresponding":false},{"id":1358409,"name":"Hussein Awada","orcid":"0000-0002-1445-7947","position":5,"is_corresponding":false},{"id":1410808,"name":"Naomi Kawashima","orcid":"0000-0002-9914-739X","position":6,"is_corresponding":false},{"id":1411215,"name":"Arooj Ahmed","orcid":null,"position":7,"is_corresponding":false},{"id":79009,"name":"Serhan Ünlü","orcid":"0000-0002-0425-5030","position":8,"is_corresponding":false},{"id":1410809,"name":"Olisaemeka Ogbue","orcid":"0000-0001-9614-6626","position":9,"is_corresponding":false},{"id":1411216,"name":"Christopher Haddad","orcid":null,"position":10,"is_corresponding":false},{"id":1358725,"name":"Aashray Mandala","orcid":null,"position":11,"is_corresponding":false},{"id":908952,"name":"Yasuo Kubota","orcid":"0000-0002-7909-5422","position":12,"is_corresponding":false},{"id":238191,"name":"Juraj Bodo","orcid":"0000-0002-4987-728X","position":13,"is_corresponding":false},{"id":480629,"name":"Genevieve M. Crane","orcid":"0000-0001-9274-0214","position":14,"is_corresponding":false},{"id":769384,"name":"Heesun J. Rogers","orcid":"0000-0001-8491-224X","position":15,"is_corresponding":false},{"id":32731,"name":"Jaroslaw P. Maciejewski","orcid":"0000-0002-6837-4346","position":16,"is_corresponding":false},{"id":348416,"name":"Valeria Visconte","orcid":"0000-0002-2993-1509","position":17,"is_corresponding":false},{"id":1233869,"name":"Luca Guarnera","orcid":"0000-0001-8293-0663","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":null,"created_at":"2026-07-19T02:51:10.077559Z","pmid":"39755843","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}