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

Abstract

Activating mutations in RAS and receptor tyrosine kinases such as KIT and FLT3 are hypothesized to cooperate with chimeric transcription factors in the pathogenesis of acute myeloid leukemia (AML). To test this hypothesis, we genotyped 150 pediatric AML samples for mutations in KIT (exons 8, 17), NRAS and KRAS (exons 1, 2) and FLT3/ITD. This is the largest cohort of pediatric AML patients reported thus far screened for all four mutations. Of the children with AML, 40% had a mutation in KIT (11.3%), RAS (18%) or FLT3/ITD (11.1%), and 70% of cases of core-binding factor (CBF) leukemia were associated with a mutation of KIT or RAS. Mutations in RAS or FLT3/ITD were frequently found in association with a normal karyotype. Patients with a FLT3/ITD mutation had a significantly worse clinical outcome. However, the presence of a KIT or RAS mutation did not significantly influence clinical outcome. We demonstrate that KIT exon 8 mutations result in constitutive ligand-independent kinase activation that can be inhibited by clinically relevant concentrations of imatinib. Our results demonstrate that abnormalities of signal transduction pathways are frequent in pediatric AML. Future clinical studies are needed to determine whether selective targeting of these abnormalities will improve treatment results.

Acute myeloid leukemia harboring t(8;21)(q22;q22): a heterogeneous disease with poor outcome in a subset of patients unrelated to secondary cytogenetic aberrations

“…32 FLT3 mutations have been detected in up to 30% of AML cases and correlate with a poor prognosis. 24,33,34 In our experience, FLT3 and RAS mutations are uncommon in AML with t(8;21)-10% or less of cases assessed were positive for FLT3 or RAS mutations. By contrast, c-KIT mutation was identified in a quarter of patients, more often in the group with short survival.…”

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

“…The aforementioned mutations in the exons 8 and 9 have have been reported in CBF-AML (D417-419insY) [40,41], kindreds with familial GISTs and mastocytosis (D 419) [42], familial mastocytosis (K509I) [43], and GISTs (ITD AY502-503) [44]. As with KITD816V, every one of the mutations in exons 8 and 9 that was tested was found to constitutively activate KIT kinase activity.…”

Clinical presentation and management practice of systemic mastocytosis. A survey on 460 Italian patients

“…The study included adult patients with diagnosis of SM for whom at minimum the information requested by WHO 2008 criteria were available: BM biopsy with immunohistochemistry staining for tryptase; serum tryptase levels; analysis of CD2/CD25 expression on mast cells by flow [10] or immunohistochemistry [11]; genotyping of cKIT (D816V) mutation. cKIT mutation was evaluated by reverse transcriptase polymerase chain reaction (RT-PCR) restriction fragment length polymorphism (RFLP) analysis [12], allelespecific ARMS-RT-qPCR [13], D-HPLC analysis followed by Sanger sequencing [14], and/or direct Sanger sequencing [15], according to center's policy. Symptoms at presentation were collected as present/absent and grouped as: constitutional symptoms, including fever, weight loss and night sweats; cutaneous, including pruritus, flushing, urticaria and angioedema; gastrointestinal, including diarrhea, abdominal/gastric pain or cramping, nausea and vomiting; musculoskeletal, including bone, articular and muscular pain and osteoporosis; allergic/anaphylactic, including hypotension, syncope/presyncope, anaphylaxis, bronchoconstriction/wheezing/dyspnea and rhinitis; neurologic, including headache and dizziness.…”