Reference Detail

Ref Type Journal Article
PMID (25015329)
Authors Iurlo A, Gianelli U, Beghini A, Spinelli O, Orofino N, Lazzaroni F, Cambiaghi S, Intermesoli T, Rambaldi A, Cortelezzi A
Title Identification of kit(M541L) somatic mutation in chronic eosinophilic leukemia, not otherwise specified and its implication in low-dose imatinib response.
Journal Oncotarget
Vol 5
Issue 13
Date 2014 Jul 15
Abstract Text Activating mutations of KIT receptor tyrosine kinase have been reported in different neoplasms. The M541L KIT substitution (KIT(M541L)) has been described to be associated with pediatric mastocytosis, to enhance growth rate of the affected cells and to confer higher sensitivity to imatinib therapy. We investigated the presence of KIT(M541L) in five males with chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), all negative for Platelet-derived growth factor-alpha (PDGFR) or PDGFRbeta abnormalities, which responded to imatinib therapy. To assess whether the mutation was constitutive or somatic in nature, we evaluated its presence analyzing either the neoplastic or normal cell population (epidermal cells or CD3-positive T lymphocytes). KIT(M541L) substitution was found in 4 out of 5 patients and in all it was somatic in nature. All patients were treated with low dose imatinib (100 mg daily orally), achieving complete and persistent clinical and hematological remission (median follow-up 74 months). One patient relapsed after 50 months. Our study strongly suggests to search for the KIT(M541L) in patients with CEL, NOS, negative for PDGFRalpha and PDGFRbeta abnormalities, to identify a subgroup of cases who may benefit from low dose imatinib therapy.


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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
M537L missense unknown KIT M537L (corresponds to M541L in the canonical isoform) lies within the transmembrane domain of the Kit protein (PMID: 16226710). M537L (M541L) is a common polymorphism that has been demonstrated to increase proliferation in the presence of ligand compared to wild-type Kit in culture (PMID: 18795925), but is not associated with tumorigenesis in the population (PMID: 16307017, PMID: 21757432) and therefore, its effect on Kit protein function is unknown.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT M541L chronic leukemia sensitive Imatinib Phase I Actionable In Phase I trials, KIT M541L has been associated with response to Gleevec (imatinib) in chronic eosinophilic leukemia, NOS (PMID: 25015329) and mastocytosis (PMID: 18795925). 25015329 18795925