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Access through your institution Buy or subscribe Systemic mastocytosis (SM) is a stem-cell-derived clonal myeloproliferation characterized by an accumulation of abnormal mast cells. A

majority of SM patients harbor the _KIT_D816V mutation, indicating its potentially important role in disease pathogenesis. _KIT_D816V activates several downstream signaling pathways

including PI3-kinase/AKT, STAT5 and ERK-1/2 that mediate its proliferative, survival and differentiation effects. SRC family kinases have an important role in stem cell factor (SCF)-induced

cell proliferation; in SCF-responsive cell lines and hematopoietic progenitor cells, LYN is associated with the juxtamembrane region of KIT, and is rapidly phosphorylated in response to SCF

stimulation.1 Coexpression of KIT with functionally defective CBL, normally a negative regulator of KIT, in murine bone marrow cells leads to generalized mastocytosis.2 Interestingly, KIT

kinase activity was dispensable for cell transformation mediated by mutant CBL; instead, transformation was dependent on the SRC family kinase, FYN. Furthermore, recent data suggest that SRC

kinase activity is important for full expression of _KIT_D816V's transforming potential; _KIT_D816V not only activates receptor kinase activity, but also subverts its substrate

specificity to confer SRC-like kinase activity.3 JAK2 also appears to be an integral component of the SCF/KIT signaling pathway; in SCF-responsive MO7e cells, JAK2 is constitutively

associated with KIT in unstimulated cells; SCF stimulation results in recruitment of JAK2 to the KIT receptor complex, and induces rapid phosphorylation of the former.4 Furthermore, JAK2

knockdown with antisense oligonucleotides resulted in marked inhibition of SCF-induced cell proliferation, thereby confirming its key role in the SCF/KIT signaling cascade. Current therapy

of SM is suboptimal and includes interferon-α and 2-chlorodeoxyadenosine, which are capable of achieving mast cell cytoreduction (reviewed by Pardanani and Tefferi5). Although several drugs

have demonstrable anti-KIT activity _in vitro_, their clinical benefit to date has been limited. Imatinib mesylate, a KIT inhibitor, does not inhibit _KIT_D816V, but has activity against

other rare SM-relevant KIT mutations, such as _KIT_F522C (transmembrane domain) and _KIT_V560G (juxtamembrane domain); consequently, it appears to have a limited role for the treatment of

adult SM. Dasatinib inhibits both juxtamembrane and activation-loop KIT mutants _in vitro_, and in addition has anti-SRC activity; it has limited activity, however, in the treatment of SM

patients and clinical responses are mostly limited to alleviation of symptoms. This is a preview of subscription content, access via your institution RELEVANT ARTICLES Open Access articles

citing this article. * PHARMACOLOGICAL TREATMENT OPTIONS FOR MAST CELL ACTIVATION DISEASE * Gerhard J. Molderings * , Britta Haenisch *  … Lawrence B. Afrin _Naunyn-Schmiedeberg's

Archives of Pharmacology_ Open Access 30 April 2016 ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access $259.00 per year only

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ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support REFERENCES * Linnekin D, DeBerry CS, Mou S . Lyn associates with the

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Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS AP is partly supported by a grant from the Henry J Predolin Foundation. TL generated and analyzed the laboratory

data; AP and AT designed the study, analyzed the laboratory data and wrote the paper. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Division of Hematology, Department of Medicine, Mayo

Clinic, Rochester, MN, USA T Lasho, A Tefferi & A Pardanani Authors * T Lasho View author publications You can also search for this author inPubMed Google Scholar * A Tefferi View author

publications You can also search for this author inPubMed Google Scholar * A Pardanani View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING

AUTHOR Correspondence to A Pardanani. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE

CITE THIS ARTICLE Lasho, T., Tefferi, A. & Pardanani, A. Inhibition of JAK–STAT signaling by TG101348: a novel mechanism for inhibition of _KIT_D816V-dependent growth in mast cell

leukemia cells. _Leukemia_ 24, 1378–1380 (2010). https://doi.org/10.1038/leu.2010.109 Download citation * Published: 20 May 2010 * Issue Date: July 2010 * DOI:

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