Clinical Significance of Alterations of the NOTCH1, FLT3 and p53 Genes in Pediatric T-Cell Acute Lymphoblastic Leukemia.

Activating mutations of the NOTCH1 gene have been reported in about 50% of T cell acute lymphoblastic leukemia (T-ALL). We performed mutation analysis of the NOTCH1, FLT3 and p53 genes by polymerase chain reaction followed by direct sequence. Mutations of the NOTCH1 were identified in 24 (30%) of 80 fresh samples and 10 (71.4%) of 14 T-ALL cell lines. Six missense mutations and 2 insertion in HD domain, 2 nonsense mutations and 6 insertions in PEST domains were found in 14 cell lines. Eight missense mutations, 9 insertions and one deletion in HD domains, 5 missense mutations, 3 nonsense mutations and 3 deletions in PEST domain were found in 80 fresh samples. The incidence of the NOTCH1 mutations is less frequent than that of previous reports. We observed about 95% of single nucleotide polymorphisms (5097 C/T) in HD domain, which is more frequent than 30% of previous report, possibly due to the racial difference. FLT3 internal tandem duplication, which is known as the poor prognostic factor in acute myeloid leukemia, were not identified in any T-ALL cell lines or fresh samples. Mutations of the p53 gene were found in 5 of 8 cell lines and 5 of 50 fresh samples. Mutations of both NOTCH1 and p53 genes were identified 3 of 8 cell lines and one of 50 fresh samples. In our study NOTCH1 mutations were not significantly associated with high WBC count and prognosis. Further studies are needed to find the association between novel genes and clinical features of pediatric T-ALL.