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Review
. 2022 Feb 8;14(3):839.
doi: 10.3390/cancers14030839.

Role of CBL Mutations in Cancer and Non-Malignant Phenotype

Davide Leardini  1 , Daria Messelodi  1   2 , Edoardo Muratore  1 , Francesco Baccelli  1 , Salvatore N Bertuccio  1   2 , Laura Anselmi  1   2 , Andrea Pession  3 , Riccardo Masetti  1
Affiliations
Review

Role of CBL Mutations in Cancer and Non-Malignant Phenotype

Davide Leardini et al. Cancers (Basel). .

Abstract

CBL plays a key role in different cell pathways, mainly related to cancer onset and progression, hematopoietic development and T cell receptor regulation. Somatic CBL mutations have been reported in a variety of malignancies, ranging from acute myeloid leukemia to lung cancer. Growing evidence have defined the clinical spectrum of germline CBL mutations configuring the so-called CBL syndrome; a cancer-predisposing condition that also includes multisystemic involvement characterized by variable phenotypic expression and expressivity. This review provides a comprehensive overview of the molecular mechanisms in which CBL exerts its function and describes the clinical manifestation of CBL mutations in humans.

Keywords: CBL; CBL syndrome; JMML; cancer predisposition; pediatric oncology.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of the CBL, CBL-b and CBL-c proteins with the relative functional domains and main phosphorylation sites. CBL and CBL-b are structurally related while CBL-c lacks the C terminal domain, including the UBA region and the proline and tyrosine rich region, mediating the binding to the SH2 and SH3 domain-containing proteins. The highly conserved N terminal region with the TKB, Linker and RF domains is crucial in the regulation of receptor and non-receptor tyrosine kinase activity.
Figure 2
Figure 2
Schematic representation of the three main molecular mechanisms of CBL-mediated signal transduction modulation. (A) CBL is hypothesized to have a dual role in JAK2 signaling. On one hand, thanks to the interaction with the mediator LNK, CBL controls the ubiquitination and consequent degradation of JAK2, on the other hand it has been highlighted how the CBL-mediated ubiquitination at the JAK2 K970 residue causes JAK2 hyperphosphorylation and the consequent activation. (B) CBL is a well-known regulator of EGFR signaling, being able to induce EGFR ubiquitination and degradation. CBL binding can be mediated also by other adaptor proteins such as Grb2 and CIN85. (C) CBL activity also has a high influence on the PI3K/AKT signaling cascade. Through the interaction with LYN, it promotes the recruitment of PIK3R1 and the subsequent PI3K phosphorylation and activation.
Figure 3
Figure 3
Known clinical manifestations of CBL mutations. The non-malignant phenotypes are an expression of germline CBL mutations. Cancers described in patients harboring a germline CBL mutation are highlighted in red. ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; CML: chronic myelomonocytic leukemia; CNS: central nervous system; JMML: juvenile myelomonocytic leukemia; MDS: myelodisplastic syndrome.
Figure 4
Figure 4
Overview of the possible pathogenesis of moyamoya disease in patients with germline CBL mutations. The role of CBL mutations in the genesis of vascular anomalies remains to be fully uncovered, particularly regarding the unknown mechanism that drives lymphocyte infiltration.
See this image and copyright information in PMC

References

    1. Kratz C.P., Jongmans M.C., Cavé H., Wimmer K., Behjati S., Guerrini-Rousseau L., Milde T., Pajtler K.W., Golmard L., Gauthier-Villars M., et al. Predisposition to cancer in children and adolescents. Lancet Child Adolesc. Health. 2021;5:142–154. doi: 10.1016/S2352-4642(20)30275-3. - DOI - PubMed
    1. Huang K.-L., Mashl R.J., Wu Y., Ritter D.I., Wang J., Oh C., Paczkowska M., Reynolds S., Wyczalkowski M.A., Oak N., et al. Pathogenic Germline Variants in 10,389 Adult Cancers. Cell. 2018;173:355–370.e14. doi: 10.1016/j.cell.2018.03.039. - DOI - PMC - PubMed
    1. Zhang J., Walsh M.F., Wu G., Edmonson M.N., Gruber T.A., Easton J., Hedges D., Aman P., Zhou X., Yergeau D.A., et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N. Engl. J. Med. 2015;373:2336–2346. doi: 10.1056/NEJMoa1508054. - DOI - PMC - PubMed
    1. Narumi S., Amano N., Ishii T., Katsumata N., Muroya K., Adachi M., Toyoshima K., Tanaka Y., Fukuzawa R., Miyako K., et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat. Genet. 2016;48:792–797. doi: 10.1038/ng.3569. - DOI - PubMed
    1. Bruzzese A., Leardini D., Masetti R., Strocchio L., Girardi K., Algeri M., Del Baldo G., Locatelli F., Mastronuzzi A. GATA2 Related Conditions and Predisposition to Pediatric Myelodysplastic Syndromes. Cancers. 2020;12:2962. doi: 10.3390/cancers12102962. - DOI - PMC - PubMed

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