A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib.

@article{Akin2004ANF,
  title={A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib.},
  author={Cem Akin and Gerard Fumo and Akif Selim Yavuz and Peter E. Lipsky and Len Neckers and Dean D. Metcalfe},
  journal={Blood},
  year={2004},
  volume={103 8},
  pages={
          3222-5
        }
}
Mutational analysis of the c-kit gene in a patient with a previously undescribed variant of mast cell disease revealed a germline mutation, Phe522Cys, within the transmembrane portion of the Kit receptor protein. Transfection experiments revealed that the mutation caused ligand-independent autophosphorylation of Kit, which was inhibited by the tyrosine kinase inhibitor imatinib mesylate. The patient's bone marrow biopsy and aspirate displayed unique pathologic features with the presence of… 

Figures from this paper

Juxtamembrane-type c-kit gene mutation found in aggressive systemic mastocytosis induces imatinib-resistant constitutive KIT activation

Different mutations, even at the same codon, in juxtamembrane domain of the c-kit gene show different inhibitory effects of imatinib, and that patients with GISTs or mast cell neoplasms possessing this Val559Ile mutation are resistant to imatinIB therapy.

Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder

Systemic mast cell activation disorder was pathogenetically characterized by two or more alterations in the Kit tyrosine kinase providing not only a means of confirming the diagnosis, but also of assessing prognosis and of starting adequate therapeutic interventions.

Advanced systemic mastocytosis: the impact of KIT mutations in diagnosis, treatment, and progression

The diagnosis and management of patients with advanced SM is discussed, including the relevance of KIT in this disease, potential therapies targeting this kinase, and criteria for measuring responses to these therapies.

Pathogenesis, clinical features, and treatment advances in mastocytosis.

Pediatric mastocytosis-associated KIT extracellular domain mutations exhibit different functional and signaling properties compared with KIT-phosphotransferase domain mutations.

This study implied different pathogenesis of pediatric versus adult mastocytosis, which might explain their diverse phenotypes.

Mutations in the fifth immunoglobulin‐like domain of kit are common and potentially sensitive to imatinib mesylate in feline mast cell tumours

In a clinical study of 10 cats with MCTs, beneficial response to imatinib mesylate was observed in 7/8 cats that had a mutation in the fifth IgD of kit in tumour cells, providing an in vivo model for paediatric mastocytosis where mutations in the sixth immunoglobulin‐like domain of kit also occur.

KIT and Mastocytosis

KIT is a receptor tyrosine kinase that is functionally relevant for hematopoiesis, mast cell development and function, gametogenesis and melanogenesis, and efforts are under way to develop and employ small molecule drugs that target mutant KIT.
...

References

SHOWING 1-10 OF 22 REFERENCES

The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations.

It is suggested that currently available KIT inhibitors may be useful in treating neoplastic cells expressing KIT activated by its natural ligand or by RT activating mutations such as gastrointestinal stromal tumors but that neither compound is likely to be effective against SAHM.

Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene.

It is shown that mastocytosis is a disorder of a pluripotential hematopoietic progenitor cell that gives rise to B cells and monocytes in addition to mast cells and that the affected clone shows variable expansion in these lineages in the peripheral blood of patients with systemic mastocyTosis.

Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors.

Sequencing of c-kit complementary DNA from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains, suggesting that the mutations contribute to tumor development.

Effect of tyrosine kinase inhibitor STI571 on the kinase activity of wild-type and various mutated c-kit receptors found in mast cell neoplasms

STI571 selectively decreases the survival of normal mast cell and of mast cell lines either with juxtamembrane c-kit mutations, but not that of tumoral mast cell from patient with SM or of mastcell lines with the D816 V mutation.

Activating c-kit gene mutations in human germ cell tumors.

Imatinib for systemic mast-cell disease