The CBL gene (Cas-Br-M (murine) ecotropic retroviral transforming sequence) is a proto-oncogene whose protein, E3 ubiquitin-protein ligase CBL, functions as a negative regulator of several signal transduction pathways including the Ras/MAP kinase signal transduction pathway. Somatic variants and translocations of this gene are found in many cancer types, including acute myeloid leukemia. The CBL gene is located on chromosome 11q23.
Juvenile myelomonocytic leukemia (JMML) is a rare form of leukemia in infancy and early childhood which is characterized by malignant transformation in the hematopoietic stem cell compartment. JMML accounts for 30% of myelodysplastic syndrome cases and 2% of all leukemias. 10 to 15% of children affected by neurofibromatosis type 1 with associated pathogenic variants in the neurofibromin gene develop JMML. Patients with Noonan syndrome or Noonan syndrome-like disorder due to germline alterations in the PTPN11, KRAS, and NRAS genes also have a predisposition to JMML. Isolated forms of JMML may include somatic PTPN11 variants as well as homozygous CBL variants.
In a few patients presenting with symptoms of Noonan syndrome, in whom pathogenic variants in genes typical for Noonan syndrome have been excluded, germline variants in the CBL gene can be detected. Most of these occur de novo. These patients may have concurrent JMML. This has been shown to be caused by a subsequent somatic LOH (loss of heterozygosity) on chromosome 11q23, where the CBL gene is located.
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