Reference Detail

Ref Type Journal Article
PMID (16015387)
Authors Goemans BF, Zwaan CM, Miller M, Zimmermann M, Harlow A, Meshinchi S, Loonen AH, Hahlen K, Reinhardt D, Creutzig U, Kaspers GJ, Heinrich MC
Title Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia.
Journal Leukemia
Vol 19
Issue 9
Date 2005 Sep
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
T417_D419delinsI deletion gain of function - predicted KIT T417_D419delinsI results in the deletion of 3 amino acids in the Ig-like C2-type domain 5 of the Kit protein from amino acids 417 to 419, combined with the insertion of an Isoleucine (I) at the same site (UniProt.org). T417_D419delinsI results in constitutive ligand-independent phosphorylation of Kit in cell culture in one study (PMID: 16015387) and therefore, is predicted to lead to a gain of Kit protein function.
T417_D419delinsRA deletion gain of function - predicted KIT T417_D419delinsRA results in the deletion of three amino acids in the extracellular domain of the Kit protein from amino acids 417 to 419, combined with the insertion of an arginine (R) and an alanine (A) at the same site (UniProt.org). T417_D419delinsRA has not been characterized, however similar Kit exon 8 mutations are activating, thus T417_D419delinsRA is predicted to lead to a gain of Kit protein function (PMID: 16015387, PMID: 15618474, PMID: 20484085).
T417_D419delinsY deletion gain of function KIT T417_D419delinsY results in the deletion of three amino acids in the Ig-like C2-type 5 domain of the Kit protein from amino acids 417 to 419, combined with the insertion of a Tyrosine (Y) at the same site (UniProt.org). T417_D419delinsY results in constitutive phosphorylation of Kit, activation of Akt and Stat pathways, and is transforming in culture (PMID: 20484085).
T417_Y418delinsH deletion gain of function - predicted KIT T417_Y418delinsH results in the deletion of two amino acids in the Ig-like C2-type 5 domain of the Kit protein from amino acids 417 to 418, combined with the insertion of an Histidine (H) at the same site (UniProt.org). T417_Y418delinsH has not been characterized, however similar Kit exon 8 mutations are activating, thus T417_Y418delinsH is predicted to lead to a gain of Kit protein function (PMID: 16015387, PMID: 15618474, PMID: 20484085).
Y418_D419delinsG deletion gain of function - predicted KIT Y418_D419delinsG results in the deletion of two amino acids in the Ig-like C2-type 5 domain of the Kit protein from amino acids 418 to 419, combined with the insertion of a Glycine (G) at the same site (UniProt.org). Y418_D419delinsG has not been characterized, however similar Kit exon 8 mutations are activating, thus Y418_D419delinsG is predicted to lead to a gain of Kit protein function (PMID: 16015387, PMID: 15618474, PMID: 20484085).
Y418_D419delinsS deletion gain of function - predicted KIT Y418_D419delinsS results in the deletion of two amino acids in the Ig-like C2-type 5 domain of the Kit protein from amino acids 418 to 419, combined with the insertion of a Serine (S) at the same site (UniProt.org). Y418_D419delinsS is predicted to lead to a gain of Kit protein function because other AML-associated KIT exon 8 deletion mutations are activating (PMID: 16015387).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT T417_D419delinsI Advanced Solid Tumor conflicting Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib mesylate) inhibited Kit phosphorylation in transformed cells over expressing KIT T417_D419delinsI in culture (PMID: 16015387). 16015387