ClinVar

In 3 unrelated patients with Noonan syndrome-like disorder and onset of juvenile myelomonocytic leukemia (JMML) in the first years of life (NSLL; 613563), Perez et al. (2010) identified a heterozygous germline 1111T-C transition in exon 8 of the CBL gene, resulting in a tyr371-to-his (Y371H) substitution. Phosphorylation of tyr371 is essential for the E3 activity of CBL and for its interaction with a number of signaling proteins. Leukemic cells from all patients showed loss of heterozygosity at chromosome 11q23, including the CBL gene. The patients all demonstrated subtle developmental defects, including dysmorphic facial features and poor growth, and 1 patient had developmental delay.

Loh et al. (2009) identified a heterozygous germline Y371H mutation in 3 unrelated children with JMML, whereas leukemic cells from all 3 patients showed homozygosity for the mutation. Additional phenotypic features were not reported. Leukemic samples from 7 additional patients contained homozygous Y371H mutations. Germline/somatic mutation status of these patients was not reported. These findings indicated that tyr371 is a hotspot for mutations associated with JMML.

Niemeyer et al. (2010) identified a heterozygous Y371H germline mutation in 7 of 21 unrelated patients with JMML. Leukemic cells from these patients showed homozygosity for the mutation, consistent with CBL functioning as a tumor suppressor gene. Two of the patients developed juvenile xanthogranulomas, and 3 had developmental delay. Family history was available from 2 patients. One had maternal relatives who died from progressive JMML and a maternal grandmother who had infantile leukemia that resolved spontaneously. The second had 2 male relatives who had died from JMML, one of whom developed small vessel vasculitis before his death. Leukemic cells from patients with the Y371H mutation showed GM-CSF hypersensitivity. In vitro studies in mouse cells with reduced Cbl expression showed that the mutant protein resulted in cytokine-independent proliferation and hypersensitivity to growth factors, associated with constitutive phosphorylation of several proteins. The mutant Y371H protein also showed a defect in E3 ligase function, supporting a role for tyr371 in maintaining the integrity of the alpha-helical structure of the linker region, which has a critical role in substrate specificity. Niemeyer et al. (2010) reported 3 additional heterozygous mutations affecting the tyr371 residue (see, e.g., 165360.0009).