The RAS gene encodes proteins that regulate signal transduc-tion by cycling between an active guanosine triphosphate (GTP) bound state and an inactive guanosine diphosphate (GDP) bound state. These proteins regulate cellular proliferation and differentiation. RAS gene mutations (mostly N-RAS) are the most common molecular abnormalities in MDS. The reported incidence of RAS mutations in MDS has varied but is perhaps 10% of MDS cases overall, with a relatively high incidence in CMML. Often N-RAS mutations are found at diagnosis but have also been found to occur during disease progression. Their real significance remains unknown, although most studies report them as unfavorable prognostic markers. It seems unlikely that they are initiating events.
Neurofibromin is the protein encoded by the gene neurofibromatosis type-1 (NF1 ). It contains a domain with sequence homology to GTPase-activating proteins. The binding of neurofibromin to RAS protein accelerates the conversion of RAS-GTP to RAS-GDP. In the majority of children with neurofibromatosis type-1 and MDS, both alleles of NF1 have been inactivated. This is further evidence for the importance of a deregulated RAS pathway in the molecular pathogenesis of MDS, and also evidence for the relevance of Knudson's model, at least in some cases of MDS.
Juvenile myelomonocytic leukemia (JMML) accounts for 30% of childhood cases of MDS. It is known that the RAS/ MAPK pathway is deregulated in JMML due to mutations in N-RAS, K-RAS or NF1 in approximately 40% of cases. Recently, germline mutations of the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP-2, were discovered to cause Noonan syndrome, a developmental disorder rarely associated with JMML. Subsequently it has been found that somatic mutations in PTPN11 account for 34% of non-syndromic (i.e. non-Noonan) JMML. The special interest here is that defects in RAS, neurofibromin and SHP-2 are all involved in the regulation of the MAPK cascade and are mutually exclusive in JMML.
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