Clonal Analysis of Multiple Point Mutations in the N‐ras Gene in Patients with Acute Myeloid Leukemia

Abstract

We have screened mutations of the N‐ras gene at codons 12, 13, and 61 in leukemia cells obtained from 100 patients with acute myeloid leukemia (AMD, and found mutated N‐ras alleles in 9 patients. We further analyzed the polyclonality of multiple N‐ras gene mutations in 4 AML patients. One patient, who had the monoclonal karyotype, t(11;17), had two types of double missense mutations at codons 13 and 61 in the same allele. Each of the remaining three patients, one of whom had t(15;17) with a monoclonal rearrangement of the retinoic acid receptor alpha and PML genes, carried two missense mutations in a relatively small population of leukemia cells. We have demonstrated that multiple clonality of the N‐ras gene is occasionally observed in leukemia with a monoclonal karyotype. These findings indicate that the N‐ras mutations may not always be characterized simply by an accumulative process and that the activated N‐ras gene alone is not sufficient to cause leukemia.

RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years

“…Although MAP kinase is constitutively (25) 254 (28) 9 (24) 187 (29) AML M3 11 (9) 170 (19) 5 (13) 129 (20) AML M4 38 (30) 173 (19) 19 (50) 131 (20) AML M5 18 (14) 87 (10) 2 (5) 59 (9) AML M6 2 (2) 19 (2) 0 (0) 13 (2)…”

“…RAS gene mutations were first reported in myeloid malignancies 17 years ago, 6 and many groups have since attempted to study their frequency in small/medium-sized cohorts of AML patients. [7][8][9][10][11][12] Several studies indicate that RAS gene mutation is associated with poor outcome in AML and myelodysplastic syndromes (MDSs), 7,13,14 but historical data sets are of insufficient size to distinguish prognostic differences between subgroups.…”

Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia

“…It has been reported that abnormalities in the RAS and p53 genes as well as the FLT3 gene are implicated in the pathogenesis of AML. [2][3][4][5][6][7] Mutations in FLT3, RAS, and p53 have been found in approximately 30%, 20%, and 5% to 10% of adult AML cases, respectively, indicating that mutations in these 3 genes are the most frequent genetic alterations in AML.…”

“…It has been reported that abnormalities in the RAS and p53 genes as well as the FLT3 gene are implicated in the pathogenesis of AML. [2][3][4][5][6][7] Mutations in FLT3, RAS, and p53 have been found in approximately 30%, 20%, and 5% to 10% of adult AML cases, respectively, indicating that mutations in these 3 genes are the most frequent genetic alterations in AML.We and several groups have demonstrated that FLT3 mutations are a strong prognostic factor in AML. [8][9][10][11][12][13][14][15][16][17][18] To date, several large-scale analyses have revealed that FLT3 mutations are essentially found in myeloid-lineage leukemia cells.…”

Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia

“…[1][2][3] Whether it is the constitutive activation of the receptor by an intrinsic receptor mutation (FLT3, kit, and fms mutations), [4][5][6] the autocrine/paracrine stimulation of the receptor by a ligand secreting tumor (VEGF receptor), 7,8 or the activation of the downstream affectors (eg, ras), [9][10][11] such activating events directly contribute to disease pathogenesis and progression. The role of individual receptors in the pathogenesis of acute myeloid leukemia (AML) has been receiving increasing attention.…”