Mutations of the p53 and ras genes in childhood t(1;19)-acute lymphoblastic leukemia

Abstract

We have investigated the alterations of p53 and ras genes including H-, K-, and N-ras genes in 22 acute lymphoblastic leukemia (ALL) cases and five cell lines carrying t(1;19) by use of polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) analysis and direct sequencing. The mutations of the p53 gene were found in 2 of 20 t(1;19)-ALL cases at diagnosis (10%), all of 4 cases at relapse (100%), and 4 of the 5 cell lines (80%). Four of the five patients who died had missense mutations at codons 49, 177, 179, and 248. In cases examined sequentially, one had the same point mutation at codon 179 at both diagnosis and relapse, and another had the same p53 gene mutation at codon 240 both in leukemic cells at relapse and in a cell line derived at that time. The other case had no mutation at diagnosis but had the mutation at codon 177 at relapse and cell lines derived from blast cells at diagnosis, suggesting that a small number of leukemic cells with the p53 gene mutation at diagnosis might have escaped PCR-SSCP analysis. In cell lines, SCMC-L9 had three point mutations in the p53 gene at codons 175, 248, and 358, whereas SCMC-L10 had frame shift at codons 209–211. One case had a rare polymorphism at codon 11. We found only one mutation of the N-ras gene that was a 2-bp substitution of GGT(Gly) to GTC(Val) at codon 13 among 22 t(1;19)-ALL cases and five cell lines. This case showed no mutation of the p53 gene and has had a good course. These results suggest that in t(1;19)-ALL, mutations of the p53 and ras genes are infrequent at diagnosis and that p53 gene alterations may be associated with relapse phase or progression of t(1;19)-ALL.

Mutations of the PTPN11 and RAS genes in rhabdomyosarcoma and pediatric hematological malignancies

“…Bone marrow or peripheral-blood (PB) specimens from 261 patients with hematological malignancies were collected from several hospitals in Japan. Twenty-two patients with de novo JMML, 17 with MDS, 85 with AML, 5 with T-ALL, 90 with B-precursor ALL and 42 with infant leukemia (6 with AML, 35 with ALL, and 1 with mixedlineage leukemia) were included (Kawamura et al, 1995;Sheng et al, 1997;Taketani et al, 2004). All these patients were diagnosed according to the French-American-British (FAB) classification system.…”

“…We also screened JMML samples and all the cell lines and fresh tumors of RMS for NRAS, KRAS, and HRAS mutations in order to investigate the frequency of RAS mutations in JMML and RMS. Because it has been shown that all RAS gene mutations are localized in exons 1 and 2, PCR was carried out to amplify exons 1 and 2 of each gene, using the primers published previously (Kawamura et al, 1995;Sheng et al, 1997), followed by direct sequencing analyses.…”

Mutational status of NRAS, KRAS, and PTPN11 genes is associated with genetic/cytogenetic features in children with B‐precursor acute lymphoblastic leukemia

“…Kawamura et al found that one of 22 t(1;19) ALL children (4.5%) had NRAS mutations 22. Urbano-Ispizua et al reported that RAS mutations were detected in only one out of 26 (3.8%) patients with BCR-ABL1 ALL 23.…”

Strong expression of p53 protein in bone marrow samples after hematopoietic stem cell transplantation indicates risk of relapse in pediatric acute lymphoblastic leukemia patients

“…6 Mutations of TP53 have been found in 2% of children at diagnosis of ALL, 7 but in 11%-28% after relapse, and are associated with lower OS, lower EFS, and higher RR, 8 indicating involvement in progression to more aggressive disease. 7,[9][10][11][12][13][14] We have previously shown an increased expression of p53 protein in children with myeloid leukemias, who relapse after HSCT. 15,16 The aim of this study was to investigate, by IHC, if alterations in the expression of p53 could be an additional prognostic marker for relapse after HSCT in pediatric ALL patients and thereby may help guiding in preemptive immunotherapy.…”