Analysis of ras gene mutations in childhood myeloid leukaemia

Abstract

Previous studies have shown that approximately 30% of adult acute myeloid leukaemias and 20% of adult acute lymphoid leukaemias contain point mutated ras oncogenes. In order to assess whether ras oncogenes are also involved in childhood leukaemias, we have used polymerase chain reaction (PCR) amplification and synthetic oligonucleotide probes to study the nature and frequency of ras gene mutations in childhood leukaemias, concentrating largely on the acute myeloid leukaemias (AML). Thirty-four childhood presentation AML DNAs were screened for mutations in and around codons 12, 61 and 117 of N-, K- and H-ras. Eight of these samples (24%) contained ras mutations. As in the adult disease, the gene predominantly involved was N-ras (6/8), with occasional activation of K-ras (2/6). The most common base change was a G----A transition at codon 12 or 13 (4/8). Of the patients with mutant ras, 4/8 were diagnosed as AML FAB subtype M5. Five of the 34 childhood AMLs analysed displayed abnormalities of chromosome 7. However, none of these cases contained a mutant ras gene. One AML patient was studied at relapse, 14 months after initial presentation. The presentation mutation (N61p3) was not detectable, although a new mutation (N13Cys) was readily identified. This observation extends our original finding with presentation and relapse samples of adult AML, in which it was uncommon for the relapse sample to contain the same ras mutation as the presentation DNA. In addition, two out of five patients diagnosed as juvenile CML, were found to harbour mutant ras.

Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia

“…18,19,36,37 RAS mutations in pediatric AML have been previously reported, albeit, in smaller cohorts of patients (10-99 patients), with frequencies of 6-37%. 35,[38][39][40][41][42] In most studies NRAS mutations were more frequent than KRAS mutations, in agreement with our own study in which 14.7% of patients had a NRAS mutation and only 3.3% a KRAS mutation.…”

Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia

“…However, mutations of the N-ras and K-ras genes occurred as frequently in childhood AML as in adult AML. 27,28 Microsatellite instabilities have not been studied in childhood AML as yet. This Sequence structure of the tandem duplicated regions.…”

In vitro profiling of the sensitivity of pediatric leukemia cells to tipifarnib: identification of T-cell ALL and FAB M5 AML as the most sensitive subsets

“…[5][6][7] In addition, RAS mutations occur in approximately 15% of pediatric patients with AML and ALL. [8][9][10][11][12][13][14][15] Mutations in HRAS have never been detected in pediatric AML or ALL samples. 8,[14][15][16] In addition to mutated RAS, signaling from other leukemia-associated oncoproteins such as KIT or fms-related tyrosine kinase 3 (FLT3) are dependent, in part, on signaling via the RAS-MAPK pathway.…”

“…[8][9][10][11][12][13][14][15] Mutations in HRAS have never been detected in pediatric AML or ALL samples. 8,[14][15][16] In addition to mutated RAS, signaling from other leukemia-associated oncoproteins such as KIT or fms-related tyrosine kinase 3 (FLT3) are dependent, in part, on signaling via the RAS-MAPK pathway. Therefore, FTIs might be effective in inhibiting proliferation and survival of leukemic cells with oncogenic events upstream of RAS or directly involving RAS family members.…”