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

Abstract

Activating mutations of receptor tyrosine kinases (RTKs) and their downstream affectors are common in acute myeloid leukemia (AML). We performed mutational analysis of FLT3, c-kit, c-fms, vascular endothelial growth factor (VEGF) receptors (Flt-1, KDR [kinase domain receptor]), and ras genes in a group of 91 pediatric patients with AML treated on Children's Cancer Group clinical trial CCG-2891. Forty-six percent of patients had activating mutations of FLT3 (24.5%), c-kit (3%), or ras (21%) genes. Mutationpositive patients had a higher median diagnostic white blood cell (WBC) count (71.5 vs 19.6 ؋ 10 9 /L; P ‫؍‬ .005) and lower complete remission rate (55% versus 76%; P ‫؍‬ .046) than mutation-negative patients. The Kaplan-Meier estimate of overall survival (OS) for patients with and without an activating mutation was 34% versus 57%, respectively (P ‫؍‬ .035). However, within this group, patients with FLT3/ALM (activation loop mutation) had good outcomes (OS, 86%). Exclusion of the FLT3/ ALM from analysis decreased the OS for the remaining mutation-positive patients to 26% (P ‫؍‬ .003). Ten of the 23 mutationpositive and 11 of the 34 mutation-negative patients received an allogeneic bone marrow transplant (BMT) in first complete remission (CR). In the mutation-positive group, the disease-free survival (DFS) for the allogeneic BMT recipients was 72% versus 23% for the 13 patients who received chemotherapy or autologous BMT (P ‫؍‬ .01). DFS for the mutation-free patients with and without allogeneic BM transplantation was 55% and 40%, respectively (P ‫؍‬ .38). Activating mutations in the RTK/ras signaling pathway are common in pediatric AML, and their presence may identify a population at higher risk of poor outcome who may benefit from allogeneic BM transplantation. (Blood. 2003;

Mutations in the receptor tyrosine kinase pathway are associated with clinical outcome in patients with acute myeloblastic leukemia harboring t(8;21)(q22;q22)

“…33,34 We found missense mutations in the activation loop of C-KIT in 10 of 37 (27%) patients with t(8;21) AML, which was within the same range as previously observed frequencies for t(8;21) and apparently higher than the incidence in overall AML cases. 12,34 In addition, three patients showed in-frame deletion and insertion mutations in exon 8, which involved codon D419 as reported by Gari et al 23 Exon 8 of the C-KIT gene encodes the fifth immunoglobulin-like extracellular domain that appears to play a role in proteolytic cleavage of the receptor and is required for structural integrity of the cell surface receptor to permit normal binding of the ligand.…”

“…Pediatric patients with all subtypes of AML carrying an activating mutation in the RTK or Ras pathways as a collective group also had a worse OS than patients without mutations. 33 Our study also provides the clinical implication that patients with RTK mutations may benefit from allogeneic HSCT. Furthermore, these findings are of significant clinical import as activating mutations in the RTK pathway can be potential therapeutic targets for specific tyrosine kinase inhibitors and Ras pathway inhibitors in patients with t(8;21) AML harboring RTK mutations.…”

“…We examined the clinical significance of the C-KIT, FLT3 and K-Ras mutations as a collective group to evaluate the role of RTK mutations in t(8;21) AML according to Meshinchi et al 33 As this approach would not be appropriate for implementation in the clinical setting, the clinical significance of each mutation must be established individually before combining these mutations into a single group. However, the signal generated by activated FLT3 or C-KIT is transduced via the MAP, PI3 kinase and STAT pathways.…”

Cooperation of activating Ras/rtk signal transduction pathway mutations and inactivating myeloid differentiation gene mutations in M0 AML: a study of 45 patients

“…[14][15][16] This is in contrast with other core binding factor (CBF) AML subtypes with the alteration of AML1 or CBFb genes through balanced translocations (t(8;21) or inv(16)). [17][18][19] These patients have very low frequency of FLT3 ITD but often have c-Kit or RAS mutation. 14,20,21 The incidence of c-Kit alteration (2%) or Ras family genes mutation (4%) and PTPN11 mutation (2%) was very low in the present series.…”

Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

“…17 FLT3 and other mutations may result in activation of the Ras/Raf/ MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways. [18][19][20][21][22][23][24] An overview of the effects of these mutations and how they may yield Achilles' heels for leukemia therapy and the treatment of other hematopoietic disorders is presented in Figure 2. It should be pointed out here, however, that the most commonly found mutation in AMLs occurs at the nucleophosmin (NPM) gene.…”