Role of CBL Mutations in Cancer and Non-Malignant Phenotype

Leardini, Davide; Messelodi, Daria; Muratore, Edoardo; Baccelli, Francesco; Bertuccio, Salvatore Nicola; Anselmi, Laura; Pession, Andrea; Masetti, Riccardo

doi:10.3390/cancers14030839

Cited by 20 publications

(19 citation statements)

References 85 publications

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“…We found that subject III.3 experienced an episode of pericarditis, occurred about 20 years after transplantation. The attribution of this pericarditis to CBL syndrome is controversial, since this clinical manifestation has not previously been reported in the disorder [ 23 ]. Moreover, subject III.3 received HSCT from the sister carrying wild-type CBL gene and a healthy immune system.…”

Section: Resultsmentioning

confidence: 99%

“…Variants in SH2B3 were also described in autoimmune diseases, particularly autoimmune type 1 diabetes [ 22 ]. CBL and SH2B3 are functionally related, contributing to the modulation of signal strength promoted by JAK proteins [ 23 ]. We herein report a family segregating pathogenic variants in CBL and SH2B3 presenting novel clinical features, particularly related to immune dysregulation.…”

Section: Introductionmentioning

confidence: 99%

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Immune dysregulation associated with co-occurring germline CBL and SH2B3 variants

et al. 2022

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Background CBL syndrome is a RASopathy caused by heterozygous germline mutations of the Casitas B-lineage lymphoma (CBL) gene. It is characterized by heterogeneous clinical phenotype, including developmental delay, facial dysmorphisms, cardiovascular malformations and an increased risk of cancer development, particularly juvenile myelomonocytic leukemia (JMML). Although the clinical phenotype has been progressively defined in recent years, immunological manifestations have not been well elucidated to date. Methods We studied the genetic, immunological, coagulative, and clinical profile of a family with CBL syndrome that came to our observation after the diagnosis of JMML, with homozygous CBL mutation, in one of the members. Results Variant analysis revealed the co-occurrence of CBL heterozygous mutation (c.1141 T > C) and SH2B3 mutation (c.1697G > A) in two other members. Patients carrying both mutations showed an ALPS-like phenotype characterized by lymphoproliferation, cytopenia, increased double-negative T-cells, impaired Fas-mediated lymphocyte apoptosis, altered cell death in PBMC and low TRECs expression. A coagulative work-up was also performed and showed the presence of subclinical coagulative alterations in patients carrying both mutations. Conclusion In the reported family, we described immune dysregulation, as part of the clinical spectrum of CBL mutation with the co-occurrence of SH2B3.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immune dysregulation associated with co-occurring germline CBL and SH2B3 variants

et al. 2022

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“…The c-cbl proto-oncogene was identified as the cellular homolog of the murine retroviral oncogene v-cbl. [22] Its gene product, Cbl, is a 906-amino acid protein that contains two distinct regions, Cbl-N and Cbl-C. [23] Composed of amino acids 1-357, Cbl-N is evolutionarily conserved and has been shown to bind many autophosphorylated tyrosine kinases in a phosphotyrosine-dependent manner. [24] Cbl-C includes evolutionarily conserved regions and a non-conserved proline-rich region capable of interacting with the Src homology 3 (SH3) domain of Src family kinases, Grb2, and Nck adaptor proteins.…”

Section: Discussionmentioning

confidence: 99%

Cbl induced ubiquitination of HER2 mediate immune escape from HER2‐targeted CAR‐T

Yang¹,

Sun²,

Deng

et al. 2023

J Biochem & Molecular Tox

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Breast cancer (BC) with high HER2 expression has higher recurrence rate and worse prognosis, and its immunotherapy is promising. Based on the high expression of HER2, develop Chimeric Antigen Receptor T‐cell (CAR‐T) and PDL‐1 immunotherapy, and study the molecular pathways of related immune cells and recurrence. HER2‐CAR‐T cells were constructed using retroviruses, and their specific recognition and immune effects on HER2+ BC cells were verified by in vivo and in vitro experiments. PDL‐1 was used as adjuvant immunotherapy, knocking down PDL‐1 in tumor cells or dendritic cells, or depleted macrophages to study immune pathways. The negative regulation of HER2 by cbl was determined by IP, ubiquitination experiments, and segmented plasmids, elucidating the molecular mechanism of HER2+ BC recurrence after immunotherapy. HER2‐CAR‐T specifically recognizes HER2‐positive tumor cells and inhibits tumor growth in vivo and in vitro, and anti‐PDL1 treatment enhances the therapeutic effect of HER2‐CAR‐T on tumors. HER2‐CART therapy eradicated solid tumors after PDL1 knockdown in dendritic cells. Immunotherapy of relapsed tumors lost HER2 expression by upregulating cbl. HER2‐CAR‐T shows specific recognition of HER2+ cells and can mediate immune response therapy with the cooperation of PDL‐1.

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“…CBL variants were of particular interest, as they were not previously reported in pediatric cancer genomics, but have been established in a variant-associated tumor predisposition syndrome (Fig. 5e) 39 . In addition, other genetic variants frequently found in cancer were identi ed including MYC or MYCN mutations (one ampli cation each, 5%) and disease speci c gene fusions including PAX3-FOXO1 in alveolar rhabdomyosarcoma (two of two patients, 100%) and EWSR-FLI1 fusions in Ewing's sarcoma (two of four patients, 50%) (Fig.…”

Section: Genomic Tumor Pro Ling Actionability and Ex Vivo Correlationmentioning

confidence: 98%

Functional Precision Medicine Enhances Clinical Outcomes of Relapsed/Refractory Pediatric and Adolescent Cancer Patients

Azzam,

Rocha,

Berlow

et al. 2023

Preprint

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Current genomics-driven precision oncology identifies actionable mutations in < 10% of cancer patients. Pediatric cancer is especially challenging due to limited mutations and fewer genomics-guided options. Functional precision medicine (FPM) addresses this by integrating genomic profiling with rapid, high-throughput functional ex vivo drug testing on live patient-derived cells. However, there is lack of FPM prospective data showing clinical utility in pediatric cancers. In this prospective, non-randomized, single-arm study (NCT03860376), we investigated feasibility and impact of FPM in pediatric/adolescent with refractory/relapsed solid and hematologic cancers. Of 25 patients, 19 (76%) had FPM data reviewed by the FPM tumor board within four weeks (FPMTB), meeting the primary outcome of the study. Additionally, six patients received FPM-guided treatment. Among these 6 patients, 83% (5 patients) experienced a greater than 1.3-fold improved progression-free survival compared to their previous therapy, and together demonstrated a significant increase in progression-free survival and objective response rate versus physician’s choice-treated patients (8 patients). Post-hoc analysis showed that patients with the same subtype of cancer do not cluster together, reinforcing the concept of optimizing cancer treatments one patient at a time (n-of-1 approach). Additionally, our study used a novel artificial intelligence/machine learning (AI/ML) platform that leveraged drug responses and sequencing data to identify novel biomarkers of drug efficacy and gain potential mechanistic insights within specific subsets of pediatric cancer patients. The findings from our proof-of-principle study illustrate the impact of FPM for relapsed/refractory pediatric/adolescent cancer patients, highlight future integrations of FPM and AI/ML, and support ongoing patient cohort expansion (NCT05857969).

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Role of CBL Mutations in Cancer and Non-Malignant Phenotype

Cited by 20 publications

References 85 publications

Immune dysregulation associated with co-occurring germline CBL and SH2B3 variants

Immune dysregulation associated with co-occurring germline CBL and SH2B3 variants

Cbl induced ubiquitination of HER2 mediate immune escape from HER2‐targeted CAR‐T

Functional Precision Medicine Enhances Clinical Outcomes of Relapsed/Refractory Pediatric and Adolescent Cancer Patients

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