scholarly journals KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis

Leukemia ◽  
2015 ◽  
Vol 29 (6) ◽  
pp. 1223-1232 ◽  
Author(s):  
M Arock ◽  
K Sotlar ◽  
C Akin ◽  
S Broesby-Olsen ◽  
G Hoermann ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mutation Analysis ◽  
Competence Network ◽  
Kit Mutation

scholarly journals Mast Cell Leukaemia: c-KIT Mutations Are Not Always Positive

2012 ◽  
Vol 2012 ◽  
pp. 1-6
Author(s):  
Magalie Joris ◽  
Sophie Georgin-Lavialle ◽  
Marie-Olivia Chandesris ◽  
Ludovic Lhermitte ◽  
Jean-François Claisse ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Leukaemia ◽  
Therapeutic Approaches ◽  
Kit Mutation ◽  
Short Survival Time ◽  
Therapeutic Choice ◽  
Molecular Abnormality ◽  
Mast Cell Leukemia ◽  
Genotypic Characteristics ◽  
Diagnostic Investigations

Mast cell leukemia (MCL) is a rare and aggressive disease with poor prognosis and short survival time. D816V c-KIT mutation is the most frequent molecular abnormality and plays a crucial role in the pathogenesis and development of the disease. Thus, comprehensive diagnostic investigations and molecular studies should be carefully carried out to facilitate the therapeutic choice. A MCL patient’s case with rare phenotypic and genotypic characteristics is described with review of major clinical biological and therapeutic approaches in MCL.

A case of ‘smouldering’ mastocytosis with high mast cell burden, monoclonal myeloid cells, and C-KIT mutation Asp-816-Val

2001 ◽  
Vol 25 (7) ◽  
pp. 627-634 ◽  
Author(s):  
John-Hendrik Jordan ◽  
Robert Fritsche-Polanz ◽  
Wolfgang R. Sperr ◽  
Gerlinde Mitterbauer ◽  
Manuela Födinger ◽  
...  
Keyword(s):  
Mast Cell ◽  
Myeloid Cells ◽  
Kit Mutation

scholarly journals c-Kit Mutation and Localization Status as Response Predictors in Mast Cell Tumors in Dogs Treated with Prednisone and Toceranib or Vinblastine

2017 ◽  
Vol 32 (1) ◽  
pp. 394-405 ◽  
Author(s):  
K.M. Weishaar ◽  
E.J. Ehrhart ◽  
A.C. Avery ◽  
J.B. Charles ◽  
R.E. Elmslie ◽  
...  
Keyword(s):  
Mast Cell ◽  
Kit Mutation ◽  
Mast Cell Tumors ◽  
Response Predictors

scholarly journals Chronic mast cell leukaemia with exon 9 KIT mutation A502_Y503dup: a rare imatinib responsive variant

2020 ◽  
Vol 13 (8) ◽  
pp. e236447
Author(s):  
Sukesh Manthri ◽  
Patrick N Costello ◽  
Koyamangalath Krishnan
Keyword(s):  
Mast Cell ◽  
Cell Leukaemia ◽  
Kit Mutation ◽  
Exon 9

t(8;21)-Positive AML with Mutant Kit Is a Novel Therapeutic Target of Imatinib Mesylate.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1164-1164
Author(s):  
Hiroya Asou ◽  
Taiichi Kyo ◽  
Toshiya Inaba
Keyword(s):  
Mast Cell ◽  
Imatinib Mesylate ◽  
Therapeutic Target ◽  
Kinase Domain ◽  
Leukemia Cells ◽  
Human Mast Cell ◽  
Cell Leukemia ◽  
Short Term ◽  
Kit Mutation ◽  
Mast Cell Leukemia

Abstract Point mutations in the kinase domain of c-Kit are frequently associated with t(8;21)-acute myeloid leukemia (AML). In our study, eleven (26 %) of 43 patients had mutations: six Asp816Val, two Asp816Tyr, one Asp816Ala, one Asp816His, and one Asn822Lys. Here, we provide evidences that proliferation of leukemia cells expressing both the AML1-ETO chimera and a c-Kit mutation heavily depends on signals originating from mutated c-Kit, and this mutation is a possible therapeutic target for imatinib mesylate. We initially investigated effects of imatinib on the growth of the Kasumi-1 cell line, which harbors both t(8;21) and a c-Kit kinase domain mutation (Asn822Lys). Imatinib inhibited autophosphorylation of c-Kit at the standard concentration (0.1 μM), and induced cell cycle arrest and apoptosis in an even faster time course than Ph1-positive cell lines treated with this drug. By contrast, growth of SKNO-1, another t(8;21)-positive leukemia cells without c-Kit mutation was not affected by imatinib. To test whether imatinib is effective for Asp816 c-Kit mutants, we isolated t(8;21)-positive fresh leukemia cells from untreated patients. Numbers of cells with an Asp816 mutant from four patients after short-term cultures in the presence of imatinib (0.1 μM, 4 days) were 20–30 % of those in the absence of imatinib, while no significant difference was observed for cells isolated from four patients without c-Kit mutation. (Viability of fresh leukemia cells without imatinib was maintained over 80% during this short-term culture.) Moreover, autophosphorylation of mutated c-Kit in leukemia cells from one patient with an Asp816 mutant was inhibited by imatinib. Our results disagree with those of previous studies, which indicated that cells with c-Kit mutations in the kinase domain are resistant to imatinib in murine IL-3-dependent cells and human mast cell leukemia cells. This discrepancy could be explained by high expression levels of c-Kit mutants in IL-3-dependent cells by powerful ectopic promoters, since overexpression of Bcr-Abl kinase is one of the major causes of resistance to imatinib in the treatment of CML patients. In addition, drug metabolism may be different between human t(8;21)-positive leukemia cells and in murine IL-3-dependent cells or mast cell leukemia cells. Although t(8;21) in AML represents a favorable prognostic indicator for achievement of cure, a substantial number of these patients relapse and eventually die of their disease. Indeed, of five patients harboring both t(8;21) and c-Kit mutations who we identified and followed up for more than five years, four relapsed. Therefore, our results suggest that imatinib would be useful for eliminating minimal residual disease in these patients after achievement of complete remission.

Effects of AMN107, a Novel Aminopyrimidine Tyrosine Kinase Inhibitor, on Human Mast Cells Bearing Wild-Type or Mutated Codon 816 c-kit.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3528-3528 ◽  
Author(s):  
Srdan Verstovsek ◽  
Cem Akin ◽  
Giles J. Francis ◽  
Manshouri Taghi ◽  
Ly Huynh ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cell Line ◽  
Cell Lines ◽  
Cellular Proliferation ◽  
Kinase Inhibitor ◽  
Wild Type ◽  
Kit Mutation

Abstract Background. Majority of adult patients with systemic mastocytosis (SM) have activating mutation in codon 816 of c-kit (CD117), a receptor on the surface of mast cells. This abnormality is responsible for the pathogenesis of the disease. Methods. We investigated the effects of a newly designed tyrosine kinase inhibitor, AMN107, by comparing its in vitro inhibitory potency on c-kit mutated mast cell lines and patient samples with that of imatinib mesylate, another tyrosine kinase inhibitor, effective in some patients with SM. Two cell lines, subclones of HMC-1 cells, were used: HMC-1560 carrying juxtamembrane domain mutation in codon 560 of c-kit, and HMC-1560, 816 carrying both codon 560 mutation and tyrosine kinase domain mutation in codon 816 of c-kit. Results. In HMC-1560 mast cell line carrying wild-type codon 816, AMN107 was as potent as imatinib in inhibiting cellular proliferation, with IC50 values of 108 and 74 nM respectively, while in HMC-1560, 816 cell line carrying 816 mutation, neither medication had an effect. AMN107 was also as effective as imatinib in inhibiting phosphorylation of c-kit tyrosine kinase in HMC-1560 cells. The inhibition of cellular proliferation was associated with induction of apoptosis in HMC-1560 cells. AMN107 in concentrations up to 1 uM had no effect on bone marrow mast cells carrying D816V c-kit mutation obtained from patients with mastocytosis. Conclusions. Our results suggest similar potency of AMN107 and imatinib in mast cells that carry wild-type codon 816, but no activity against codon 816 mutation carrying cells.

Detection of Activated STAT5 in Neoplastic Mast Cells in Patients with Systemic Mastocytosis: Role of c-kit D816V.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3515-3515 ◽  
Author(s):  
Karoline Sonneck ◽  
Matthias Mayerhofer ◽  
Karoline V. Gleixner ◽  
Marc Kerenyi ◽  
Maria-Theresa Krauth ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Systemic Mastocytosis ◽  
Cell Leukemia ◽  
Oncogenic Signaling ◽  
Kit Mutation ◽  
Knock Out ◽  
Mast Cell Leukemia ◽  
Kit D816v

Abstract Recent data suggest that activated STAT5 contributes to growth and differentiation of mast cells (MC) and that STAT5-knock out mice are MC-deficient. We have recently shown that constitutively activated STAT5 acts as a potent oncogenic signaling molecule in hematopoietic progenitor cells (Cancer Cell2005;7:87–99). In the present study, we examined the expression of activated STAT5 in neoplastic MC in systemic mastocytosis (SM) and asked whether the SM-related oncogene c-kit D816V is involved in STAT5-activation. For the immunohistochemical detection of activated tyrosine phosphorylated STAT5 (P-Y-STAT5), we used the specific monoclonal antibody AX1 (Advantex) which does not react with inactive STAT5. In all patients with SM tested (indolent SM, n=11; smouldering SM, n=2; aggressive SM, n=1; mast cell leukemia, n=1; all exhibiting c-kit D816V), MC were found to display P-Y-STAT5. Expression of activated STAT5 was also demonstrable in the c-kit D816V-positive mast cell leukemia-derived cell line HMC-1. The reactivity of HMC-1 cells with AX1 antibody was abrogated by a STAT5-specific blocking-peptide. To define the role of c-kit D816V in STAT5-activation, Ba/F3 cells with doxycycline-inducible expression of c-kit D816V (Ton.kit) were employed. In these cells, induction of c-kit D816V was followed by a massive increase in phosphorylated STAT5 as determined by a specific DNA-binding assay, whereas the total amounts of STAT5-mRNA and of the STAT5-protein showed only a slight increase or remained unchanged. In summary, these data show that neoplastic MC in SM express activated STAT5 (P-Y-STAT5), and that the transforming c-kit mutation D816V leads to persistent activation of STAT5 in these cells.

Phase II Trial of the Tyrosine Kinase Inhibitor PKC412 in Advanced Systemic Mastocytosis: Preliminary Results.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3609-3609 ◽  
Author(s):  
Jason Gotlib ◽  
Tracy I. George ◽  
Andrea Linder ◽  
Alisa Ruddell ◽  
Sylvia Quesada ◽  
...  
Keyword(s):  
Mast Cell ◽  
Partial Response ◽  
Tyrosine Kinase ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Systemic Mastocytosis ◽  
High Rate ◽  
Minor Response ◽  
Kit Mutation ◽  
Grade 3

Abstract Background: Advanced forms of systemic mastocytosis (aggressive systemic mastocytosis [ASM] and mast cell leukemia [MCL]) are myeloproliferative disorders with few treatment options and a poor prognosis. In the majority of patients (pts), the pathogenesis of ASM/MCL is related to constitutive activation of the receptor tyrosine kinase (TK) KIT, due to an aspartate to valine mutation within protein codon 816 (D816V). D816V KIT is imatinib resistant both in vitro and in vivo. We demonstrated that PKC412 (N-benzoyl-staurosporine), a structurally different KIT TK inhibitor, can block the growth of D816V KIT-transformed cells at a low 50% inhibitory concentration of 30-40 nM (vs. imatinib > 1 uM). In addition, we treated a MCL pt with PKC412 on a compassionate basis, resulting in a good partial response (Gotlib et al, Blood. 2005; 106:2865-70). Therefore, we initiated a phase II study designed to assess PKC412 efficacy and safety in ASM/MCL pts. Methods: PKC412 100 mg bid was administered in 28-day cycles. Pts without a major response (MR) or partial response (PR) by Valent criteria after 2 cycles were discontinued. Results: To date, 11 ASM pts (n=6 male) have been enrolled, 7 with an associated CMML or mixed MDS/MPD. Median age at entry was 62 yrs (range 30–72); the median # of prior therapies was 1 (range 0–3). Efficacy: Currently, 9 pts are evaluable for efficacy. Responses were observed in 6/9 (67%) pts, including 2 pts with a MR (both incomplete remission), and 4 pts with a PR (3 good PR, 1 minor response). Three pts were discontinued after 2 cycles (2 progressive disease, 1 stable disease). The 2 MRs consisted of resolution of hypoalbuminemia and correction of the platelet count to >100,000/mm3 in one pt, and normalization of splenomegaly with a 69% decrease in serum tryptase in the second pt. The 3 good PRs includedalmost complete resolution of large-volume ascites,> 50% reduction in palpable hepatosplenomegaly, and>50% reduction in direct hyperbilirubinemia.Serum tryptase decreased by 60–70% in 2 of these pts. All MRs and good PRs were accompanied by a marked improvement in performance status. Median duration of treatment in responders is 4.5 cycles (2+ - 11+). Bone marrow (BM) mast cell (MC) burden was stable to slightly decreased in responders; in 1 PR pt, the BM MC burden decreased from 50% to 20% with loss of expression of the neoplastic mast cell surface marker CD25. Safety: PKC412 was generally well tolerated. Non-hematologic AEs included grade 1–2 nausea and/or vomiting (N/V), and less commonly diarrhea, fatigue, and headache (HA). Worsening of pre-existing anemia developed in 2 pts (grade 2 and 3, n=1 each). Dose reduction to 50 mg bid was undertaken in 3 pts for grade 3 thrombocytopenia, grade 2 N/V, and grade 2 HA. Two pts discontinued therapy after 4 cycles (1 for grade 3 fatigue and 1 for grade 2 N/V). Conclusion: PKC412 demonstrates a high rate of MRs and PRs in this initial cohort of advanced SM pts, supporting further accrual in this Simon two-stage trial. Ongoing biologic investigations include pharmacokinetics, KIT mutation and phosphorylation status, serum KIT/KIT ligand levels, and ex vivo effects of PKC412 with BM MC.

Sign in / Sign up

Export Citation Format

Share Document