Noonan Syndrome
Dongyou Liu in Handbook of Tumor Syndromes, 2020
CBL syndrome (or Noonan syndrome-like disorder with or without JMML) is caused by germline mutations in the CBL gene encoding a ubiquitously expressed E3 ubiquitin ligase that mediates the association of ubiquitin with activated RTK, which is necessary for receptor internalization and degradation. CBL mutations reduce the turnover of activated RTK and increase ERK activation in the RAS/MAPK pathway. Apart from facial features, impaired growth, developmental delay, and cryptorchidism that are also observed in Noonan syndrome, CBL syndrome is associated with an enlarged left atrium, transient chaotic ventricular dysrhythmia, delayed brain myelination, cerebellar vermis hypoplasia, bicuspid aortic valve with stenosis, average adult height, mitral valve insufficiency, and clear predisposition to JMML.
Lysosomal Vitamin B12 Trafficking
Bruno Gasnier, Michael X. Zhu in Ion and Molecule Transport in Lysosomes, 2020
The cobalamin coenzyme synthesis assay monitors the uptake of radio-labelled, non-physiological cyano-([57Co])-Cbl, and follows its intracellular conversion to hydroxo-Cbl and ultimately the cofactor forms adenosyl-Cbl and methyl-Cbl (Figure 7.2). It is therefore sensitive to the entire cellular metabolic Cbl pathway, including processing through the lysosomal compartment, and allows one to pinpoint the nature of the cellular defect of Cbl metabolism, regardless of its protein/organelle of nature. From the point of view of lysosomal investigation, this allows the researcher to assay any condition (e.g. small molecules, gene knock-out) that may result in alteration of lysosomal Cbl release. This method was originally described by Mahoney and Rosenberg (Mahoney and Rosenberg, 1971) and modified by Mellmen and colleagues (Mellman et al., 1978). Here we present the updated method with our own modifications including the reagents and equipment used in our laboratory. Uptake, transport and modification of Cbl in the cobalamin cofactor synthesis assay. Radio-labelled cyano-Cbl (CN-Cbl) is provided to the cells bound to transcobalamin (TC). Cbl transported through the cells is modified to hydroxo-Cbl (OH-Cbl) and finally converted to the cofactor forms methyl-Cbl (Me-Cbl) and adenosyl-Cbl (Ado-Cbl).
Cobalamin C, D, F, G diseases; methylmalonic aciduria and variable homocystinuria
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
Methionine synthase activity is deficient in Cbl E and G diseases. This enzyme catalyzes the transfer of a methyl of 5-methyltetrahydrofolate to homocysteine. Mutations in the gene coding for this enzyme cause Cbl G disease. In Cbl E disease, the mutations are in the gene for methionine synthase reductase which maintains the synthase in its reduced state.
Sorafenib regulates c-CBL gene-mediated chemoresistance in acute myeloid leukemia cells
Published in Hematology, 2023
Qixin Sun, Bingyi Wu, Fanyi Meng, Qianqian Yao, Zhiwei Huang, Jianhui Xu, Zhigang Zhu
Overall, we found c-CBL gene expression is related to cell chemoresistance; the lower the gene expression is, the higher the cell chemoresistance is. Clinical data come from relapsed and refractory patients also confirm this finding. Salvage therapy containing sorafenib can lead to the downregulation of CBL protein expression in leukemia cells. From the perspective of CBL protein mediated chemoresistance, this treatment is not suitable for all patients. For patients with high c-kit expression, we can deduce the level of CBL protein have already in its lowest level in these cells, there is no room to further decline, so the adverse effect of sorafenib is limited, and patients may benefit from further inactivation of tyrosine kinase signaling, and our previous clinical observations have already confirmed this phenomenon. In addition, we found MDR1 maybe participates in c-CBL gene mediated chemoresistance, it is worth discussing in the future as more and more tyrosine kinase inhibitors are used in the clinic.
Overproduction of IL-2 by Cbl-b deficient CD4+ T cells provides resistance against regulatory T cells
Published in OncoImmunology, 2020
SeongJun Han, Douglas C. Chung, Michael St. Paul, Zhe Qi Liu, Carlos Garcia-Batres, Alisha R. Elford, Charles W. Tran, Laurence Chapatte, Pamela S. Ohashi
Recently, a genome-wide CRISPR screen of primary human T cells has identified Cbl-b as the top candidate to enhance T cell activation, proliferation and tumor cell killing in vitro.60 This is consistent with previous findings which identify Cbl-b as an important gene regulating autoimmunity and anti-tumor immunity in mice.46,47,53 In this study, we focused on CD4+ T cells and explored the mechanism of Cbl-b in mediating T cell resistance to Treg cells. We show that hyper-secretion of IL-2 by Cbl-b KO CD4+ T cells and upregulation of CD25 increase effector T cell exposure and sensitivity to IL-2 (Figure 7a,b). Increased exposure to IL-2 signaling then counteracts the previously established ability of Treg cells in sequestering IL-2 required for effector T cell proliferation and survival.15,61 Furthermore, while other cytokines can mediate Treg cell resistance, we found that IL-2 served as the central molecule essential for cytokine-driven Treg resistance.
Novel approaches to diagnosis and treatment of Juvenile Myelomonocytic Leukemia
Published in Expert Review of Hematology, 2018
Franco Locatelli, Mattia Algeri, Pietro Merli, Luisa Strocchio
Germ line mutations in CBL, found in as much as 15% of all cases, have been described in children showing several congenital abnormalities that overlap those observed in NF1, NS, and Legius syndrome [9,41,49]. In these patients, JMML appears as the result of loss of heterozygosity (LOH) for the CBL locus in hematopoietic stem/progenitor cells. CBL encodes a member of a family of RING finger proteins, which functions as an E3 ubiquitin ligase and negatively regulates signaling by tyrosine kinases [50]. Using single-nucleotide polymorphism arrays, a region of 11q isodisomy containing the CBL gene was detected in JMML cells, leading to the identification of CBL mutations in 27 of 159 JMML patients [41]. CBL mutations targeting the Y371 amino acid in the linker region have been more commonly reported in JMML and are rare in other myeloid neoplasms [51]. The observation that CBL mutations and other Ras pathway-associated mutations were mutually exclusive suggested the role of CBL in deregulating the Ras pathway in JMML [49,52].
Related Knowledge Centers
- Cell Signaling
- Protein Domain
- Ubiquitin
- Ubiquitin Ligase
- Carcinogenesis
- Acute Myeloid Leukemia
- Murine Leukemia Virus
- Tyrosine Kinase
- N-Terminus
- Cbl Tkb Domain