Germline mutations of the CBL gene : a new RASopathie with predisposition to juvenile myelomonocytic leukemia (JMML)

Hélène Cavé, PharmD, PhD
Genetics department, CHU Robert Debré and INSERM U940, Universitary institute of Haematology, Paris, France

CBL, an E3 ubiquitin ligase and multi adaptor protein, controls proliferative networks by downregulating the growth factor receptor signaling cascades in various cell types. CBL missense mutations have recently been found in 10-15% patients having juvenile myelomonocytic leukemia (JMML), an aggressive myelodysplastic and myeloproliferative neoplasm of early childhood. The majority of these patients displays germline heterozygous CBL mutations. The process of tumorigenesis is in line with the classical Knudson hypothesis for tumor suppressor genes. The germline mutation, inherited from the parents in about half of cases, represents the first hit. Somatic loss of heterozygosity of 11q23.3, due to acquired somatic uniparental isodisomy is the second hit, positively selected for in JMML cells. Noteworthy, a mutation targeting Y371, is found in about half of the patients with germline CBL mutation who develop JMML.

Besides JMML predisposition, germline CBL mutation defines a new dominant genetic condition with a markedly variable phenotype combining dysmorphic features, hyperpigmented skin lesions, cryptorchidism, cardiopathy, neurological lesions, developmental delay, postnatal growth retardation, and autoimmune phenomena. Some clinical features are reminiscent of Noonan syndrome (NS) or type 1-neurofibromatosis (NF1), and CBL mutations are found in about 1% of patients suspects of NS. However, the “CBL syndrome” only partially overlaps with NS and probably remains largely underdiagnosed in patients who do not display hematological features. Further studies will permit to refine the clinical description of patients with this syndrome and to better appreciate the risk of leukemia or other malignancies associated with it.

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