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	Vol	Issue	Date	Pages	Journal Short Title
Leukemia	19	9	2005 Sep	1536-42	Leukemia

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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
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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Gene	Variant	Impact	Protein Effect	Variant Description
KIT	T417_D419delinsI	indel	gain of function - predicted	KIT T417_D419delinsI results in the deletion of three amino acids in 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 (PMID: 16015387), and therefore, is predicted to lead to a gain of Kit protein function.
KIT	T417_D419delinsRA	indel	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 (PMID: 16015387, PMID: 20484085), and therefore, is predicted to lead to a gain of Kit protein function.
KIT	T417_D419delinsY	indel	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 (PMID: 16015387), activation of Akt and Stat pathways, and is transforming in culture (PMID: 20484085).
KIT	T417_Y418delinsH	indel	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 a histidine (H) at the same site (UniProt.org). T417_Y418delinsH has not been characterized, however similar Kit exon 8 mutations are activating (PMID: 16015387, PMID: 20484085), and therefore, is predicted to lead to a gain of Kit protein function.
KIT	Y418_D419delinsG	indel	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 (PMID: 16015387, PMID: 20484085), and therefore, is predicted to lead to a gain of Kit protein function.
KIT	Y418_D419delinsS	indel	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 has not been characterized, however similar Kit exon 8 mutations are activating (PMID: 16015387, PMID: 20484085), and therefore, is predicted to lead to a gain of Kit protein function.

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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

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