ライフサイエンスコーパス: KIT

1 KIT and PDGFRA mutations account for 85-90% of GISTs; su

2 KIT D816V-mutated MSCs were detected in 22 of 83 cases.

3 KIT exon 11 deletion mutations, deletions that involved

4 KIT exon 11 mutations were further grouped as deletion o

5 KIT is targeted for cancer therapy in gastrointestinal s

6 KIT knockdown also increased RAS/MAPK pathway activation

7 KIT mutations were detected in only 10 (30%) of 33 patie

8 KIT tyrosine kinase inhibitors (TKI) are superior to con

9 KIT, PDGFRA, NF1 and SDH mutations are alternate initiat

10 ing of the regenerated donor Lin(-) SCA-1(+) KIT(+) (LSK) cells shows dysregulated expression of ZEB1

11 eceptor tyrosine kinase, such as the exon 11 KIT V559Delta mutation.

12 aring mast cells (MCs) often lacking exon 17 KIT mutations.

13 P53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%).

14 in patients with metastatic GIST harboring a KIT exon 11 mutation.

15 trial to evaluate the effect of imatinib, a KIT inhibitor, on airway hyperresponsiveness, a physiolo

16 hat have converted, during TKI-therapy, to a KIT-independent state.

17 ratio [HR], 9.8; P = .001), together with a KIT D816V VAF >= 1% in bone marrow (BM) (HR, 10.1; P = .

18 3-year group), 274 (80.4%) had GISTs with a KIT mutation, 43 (12.6%) had GISTs that harbored a PDGFR

19 , whereas targeted DNMT1 depletion abrogates KIT signaling cascade through Sp1/miR-29b network.

20 e treatments for cancers driven by activated KIT and other RTKs may rely on clear understanding of th

21 The discovery of activated KIT mutations in gastrointestinal (GI) stromal tumors (G

22 oplastic mast cells harboring the activating KIT mutation D816V in the bone marrow and other internal

23 therapy in their ability to control advanced KIT-mutant disease.

24 reatment concepts use drugs directed against KIT and other relevant targets in neoplastic mast cells

25 and multikinase inhibitors directed against KIT D816V and other key signaling molecules.

26 PDGFRA-mutant GIST, similar progress against KIT/PDGFRA wild-type GIST, including mutant BRAF-driven

27 ly, LMTK3 silencing reduced viability of all KIT-mutant cell lines tested, even those with drug-resis

28 transcripts POU5F1, TFAP2C, LIN28A, ALPP and KIT were also reduced by ibuprofen.

29 inducing the upregulation of IL23R, CCR6 and KIT messenger RNA in these cells.

30 We demonstrated that DNMT1 and KIT form a positive regulatory loop, in which ectopic DN

31 Overexpression of DNMT1 and KIT is prevalent in lung cancer, yet the underlying mole

32 ncer pathogenesis, whether and how DNMT1 and KIT orchestrate lung tumorigenesis are unclear.

33 ntiation, but retained responses to EGFR and KIT.

34 inhibition, and more so to combined FGFR and KIT inhibition, validating the functional significance o

35 ly druggable, mutations in the EGFR, MET and KIT oncogenes.

36 targets IKBKB, WEE1, FGF2, RAD50, MSH2, and KIT.

37 PDGFRA mutations and KIT exon 11 insertion or duplication mutations were asso

38 nk between early driver mutations in RAS and KIT and the widespread copy number events by which TGCT

39 ing consensus, our results show that SCF and KIT signaling are dispensable for early mast cell develo

40 ive, mature, and proliferate without SCF and KIT signaling in vitro.

41 n that mast cell progenitors require SCF and KIT signaling throughout differentiation.

42 ssumed to require stem cell factor (SCF) and KIT signaling during differentiation for the formation o

43 ), size of the largest lesion (smaller), and KIT mutation (exon 11) were significant prognostic facto

44 S-tryptase and KIT D816V allele burden were monitored.

45 class of KIT mutants responded well to anti-KIT antibody treatment alone or in combination with a lo

46 n of TKI with anti-KIT antibodies or to anti-KIT toxin conjugates, respectively.

47 onded well to a combination of TKI with anti-KIT antibodies or to anti-KIT toxin conjugates, respecti

48 EAB) at month 6, patients were classified as KIT responders (>/=25%, n = 17) or KIT nonresponders (<2

49 studies of 20 cases originally classified as KIT/PDGFRA wild-type GIST revealed that 17 (85.0%) harbo

50 Only, the siliceous material labelled as KIT-6 was not suitable for wine fining.

51 d increased tumor oncogenesis and associated KIT-dependent STAT activation.

52 lonal emergence of the resistance-associated KIT V654A mutation.

53 on of KIT oncoproteins, and therefore become KIT-independent and are consequently resistant to KIT-in

54 th molecular data (serial monitoring of both KIT D816V variant allele frequency and NGS panels) to le

55 In addition, CCL2 secreted by KIT D816V(+) mast cells was found to promote the migrati

56 SM), disease evolution is often triggered by KIT mutations (D816V in >80% of cases) and by additional

57 red mutations that constitutively activate c-KIT is a significant challenge in the treatment of patie

58 he activation loop to switch the activated c-KIT back to its structurally inactive state.

59 g how a compound can inhibit the activated c-KIT by switching back to its inactive state through a se

60 nhibitor against unactivated and activated c-KIT.

61 Although c-KIT(+) endothelial cell (EC) progenitors are abundant in

62 rolase), ERalpha (a nuclear receptor), and c-KIT (a kinase).

63 r-like protein (PDGFR) alpha and beta, and c-KIT tyrosine kinases.

64 Expression of FOXF1 and c-KIT was decreased in the lungs of infants with BPD.

65 KIT proteins (c-KIT(WT), c-KIT(D816V), and c-KIT(D816H)) to select aptamers from a random RNA pool th

66 me B and CD107A), resistance to apoptosis (c-KIT and Bcl2), and enhanced stemness (beta-catenin and L

67 SPRED1 binds directly to both c-KIT and to the RasGAP, neurofibromin, whose function is

68 seq) in SSEA4(+) hSSCs and differentiating c-KIT(+) spermatogonia, and performed validation studies v

69 ve warhead is employed to target Cys788 in c-KIT, where acrylamide has previously failed to form cova

70 nd induced apoptosis by targeting c-KIT in c-KIT-mutant GIST cell lines.

71 y elucidate its high potency in inhibiting c-KIT kinase activity.

72 eroxia.Conclusions: Cell therapy involving c-KIT(+) EC progenitors can be beneficial for the treatmen

73 Two receptor tyrosine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutat

74 duced gene activation include c-MYC, KRAS, c-KIT, HIF-1alpha, PDGF-A and hTERT.

75 bit the in vitro kinase activity of mutant c-KIT(D816V) with an IC(50) value that is 9-fold more pote

76 tion against single or double mutations of c-KIT developed in GISTs.

77 ed against the kinase domain of a group of c-KIT proteins (c-KIT(WT), c-KIT(D816V), and c-KIT(D816H))

78 urvival, proliferation, and engraftment of c-KIT(+) EC progenitors in the neonatal lung.Measurements

79 neonatal hyperoxia decreased the number of c-KIT(+) EC progenitors.

80 Adoptive transfer of c-KIT(+) ECs into the neonatal circulation increased lung

81 The transcriptomic signature of c-KIT(+) ECs was conserved in mouse and human lungs and en

82 d apoptosis and decreased proliferation of c-KIT(+) ECs.

83 ed that 15a inhibited the proliferation of c-KIT- and FLT3-driven AML cells in vitro and in vivo.

84 use basal cells selected for expression of c-KIT.

85 inase domain of a group of c-KIT proteins (c-KIT(WT), c-KIT(D816V), and c-KIT(D816H)) to select aptam

86 g.Measurements and Main Results: Pulmonary c-KIT(+) EC progenitors expressing PECAM-1, CD34, VE-Cadhe

87 tworks shared by human and mouse pulmonary c-KIT(+) EC progenitors.

88 e prototypes of stem cell factor receptor (c-KIT)-driven cancer.

89 a cells, we showed activation of EPH RTKs, c-KIT, and SFK members independent of mTORC1/2 activation.

90 eration and induced apoptosis by targeting c-KIT in c-KIT-mutant GIST cell lines.

91 We show that c-KIT signaling regulates self-renewal capacity and preven

92 d the potential to distinguish between the c-KIT kinases by modulating the phosphorylation activity o

93 or of a G-rich sequence located within the c-KIT proximal promoter (kit2) in the presence of monovale

94 The c-KIT receptor represents an attractive target for cancer

95 hereas the P/-8-kb enhancer targeted TIE2+/c-KIT+/CD41- endothelial cells that were enriched for hema

96 eover, 10a can effectively inhibit various c-KIT mutants and the proliferation of several GIST cell l

97 n unknown.Objectives: To determine whether c-KIT(+) EC progenitors stimulate alveologenesis in the ne

98 vealed the unique binding mode of 15a with c-KIT and may elucidate its high potency in inhibiting c-K

99 n of a group of c-KIT proteins (c-KIT(WT), c-KIT(D816V), and c-KIT(D816H)) to select aptamers from a

100 management of GIST harboring the most common KIT and PDGFRA mutations, optimal management of other ge

101 ristics, including the presence of the D816V KIT mutation.

102 rmore, targeting of LMTK3 with siRNA delayed KIT-dependent GIST growth in a xenograft model.

103 We detected KIT and/or NRAS mutation, known as frequently mutated ge

104 FLT3, NRAS, PTPN11, WT1, TET2, DHX15, DHX30, KIT, ETV6, KRAS), with variable persistence at relapse.

105 perties and responds distinctly to different KIT inhibitors.

106 d immune profiles capable of differentiating KIT and PDGFRA-mutant GISTs, and also identified additio

107 ion program, which was also seen with direct KIT inhibition using a tyrosine kinase inhibitor (TKI).

108 ies and Figla ablation dramatically disrupts KIT, NOBOX, LHX8, SOHLH1 and SOHLH2 abundance.

109 or binimetinib further decreased downstream KIT signaling.

110 ion is not unspecific, because ligand-driven KIT internalization is not accompanied by CD13 internali

111 that arise (or that are selected for) during KIT TKI treatment.

112 most harbor an activating mutation in either KIT or platelet-derived growth factor A ( PDGFRA).

113 genesis, reduced proliferation of epithelial KIT(+) progenitors, and increased expression of a target

114 by mesenchymal cells can regulate epithelial KIT(+) progenitor cell expansion during murine salivary

115 elanocytes during development, and excessive KIT activity hyperactivates the RAS/MAPK pathway and can

116 of type 2 immune responses that also express KIT and colocalize with mast cells at barrier tissue sit

117 ing mutations in the mast cell growth factor KIT gene cause cutaneous mastocytosis in young children

118 hms, and discovered additional ITDs in FLT3, KIT, CEBPA, WT1 and other genes.

119 , localized GISTs with mutation analysis for KIT and PDGFRA performed centrally using conventional se

120 ptase determination, mutational analysis for KIT D816V, and bone marrow evaluation to rule out a clon

121 ry regions of the KIT enhancer essential for KIT gene expression and GIST cell viability.

122 pigenetic regulator of genes responsible for KIT(+) progenitor expansion during organogenesis.

123 signal transduction pathways emanating from KIT for tumorigenesis, the oncogenic Kit(V558Delta) muta

124 Functionally, KIT and DNMT1 co-expression promotes, whereas dual inact

125 High KIT mutant allele ratios defined a group of t(8;21) AML

126 man 4 feline sarcoma viral oncogene homolog (KIT) receptor tyrosine kinase.

127 ified a panel of 6 genes, ALDH1A1, HSP90AB1, KIT, KRT16, SPRR3 and TMEM45B whose expression values di

128 hylation; in turn, DNMT1 dysfunction impairs KIT kinase signaling.

129 d cell viability and increased cell death in KIT-dependent, but not KIT-independent GIST and melanoma

130 identified distinctive biologic features in KIT-independent, imatinib-resistant GISTs as a step towa

131 Cyclin D1 inhibition in KIT-independent GISTs had anti-proliferative and pro-apo

132 broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with

133 or older with known WT GIST (no mutations in KIT or PDGFRA) were recruited; 116 patients with WT GIST

134 quently mutated, with recurrent mutations in KIT, TSC2, and MAPK pathway genes (BRAF, KRAS, and NRAS)

135 se inhibitors to overcome these mutations in KIT.

136 escribe its role as a novel KIT regulator in KIT-mutant GIST and melanoma cells.

137 used by somatic KIT mutations that result in KIT receptor tyrosine kinase constitutive activity, whic

138 ght to identify novel therapeutic targets in KIT-mutant GIST and melanoma cells using a human tyrosin

139 ators, enhancers, and chromosome topology in KIT-mutant, PDGFRA-mutant and SDH-deficient GISTs.

140 BBI treatment in KIT-dependent GIST cells produced genome-wide changes in

141 onic and adult cardiac stem cells, including KIT(+), PDGFRalpha(+), ISL1(+)and SCA1(+)cells, side pop

142 ivating tyrosine kinase signaling (including KIT, N/KRAS, and FLT3) were frequent in both subtypes of

143 The small molecule imatinib inhibits KIT and has been a mainstay of therapy in GIST.

144 Masitinib inhibits KIT and LYN kinases that are involved in indolent system

145 e multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis.

146 Imatinib treatment, which inhibits KIT signaling, depletes mast cells in vivo.

147 ng 4-week intermittent fasting (CALU, INTS6, KIT, CROCC, PIGR), and 1 week after 4-week intermittent

148 The receptor tyrosine kinase KIT promotes survival and migration of melanocytes durin

149 ng mutations in the receptor tyrosine kinase KIT.

150 KIT proto-oncogene receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor alpha (

151 IT proto-oncogene, receptor tyrosine kinase (KIT), and platelet-derived growth factor receptor alpha

152 ons in the related receptor tyrosine kinases KIT and PDGFRA.

153 testinal stromal tumors (WT-GISTs) that lack KIT or PDGFRA mutations represent a unique subtype of GI

154 ntestinal stromal tumors (GISTs), which lack KIT and PDGFRA gene mutations, are the primary form of G

155 D842V mutation or patients with GIST lacking KIT and PDGFRA mutations.

156 Here, we show that each of the six major KIT oncogenic mutants exhibits different enzymatic, cell

157 e subtype of advanced systemic mastocytosis, KIT mutation status, or exposure to previous therapy.

158 ed phase 2 study, midostaurin, a multikinase/KIT inhibitor, demonstrated an overall response rate (OR

159 th midostaurin, an orally active multikinase/KIT inhibitor now approved for advSM in the United State

160 The approval of the multikinase/KIT inhibitor midostaurin has validated the paradigm of

161 Multilineage KIT involvement and multimutated clones are characterist

162 All MSC-mutated patients had multilineage KIT mutation (100% vs 30%, P = .0001) and they more freq

163 frequently driven by auto-activated, mutant KIT and have durable response to KIT tyrosine kinase inh

164 igned to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloprolife

165 on that cell-autonomous expression of mutant KIT in the ICC lineage leads to GIST.

166 Expression and activity of mutant KIT is essential for driving the majority of GIST neopla

167 sing molecules for the inhibition of mutated KIT.

168 ificantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8.

169 ck of metabolic response (P < 0.001) and non-KIT exon 11-mutated GISTs (P < 0.001).

170 anagement in GIST patients harboring the non-KIT exon 11 mutation and should be considered the standa

171 PRKCQ, but not KIT, was a negative regulator of cyclin D1 expression, w

172 creased cell death in KIT-dependent, but not KIT-independent GIST and melanoma cell lines.

173 antitumour activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D

174 summary, we have identified CCL2 as a novel KIT D816V-dependent key regulator of vascular cell migra

175 TK3) and herein describe its role as a novel KIT regulator in KIT-mutant GIST and melanoma cells.

176 ed a MEGS with five genes (FLT3, IDH2, NRAS, KIT, and TP53) and a MEGS (NPM1, TP53, and RUNX1) whose

177 sults demonstrate the existence of a nuclear KIT-driven NFKBIB-RELA-KIT autoregulatory loop in GIST t

178 ST cells without knowing the role of nuclear KIT in GIST tumorigenesis.

179 , we first identified the binding of nuclear KIT to the promoter of NFKB inhibitor beta (NFKBIB) by c

180 T has been revolutionized with the advent of KIT-directed cancer therapies.

181 Mutations and amplification of KIT are also common.

182 ttern of inactivation of the X-chromosome of KIT-mutated BM mast cells (64% vs 0%; P = .01) vs other

183 One class of KIT mutants responded well to anti-KIT antibody treatmen

184 A second class of KIT mutants, including a mutant resistant to imatinib tr

185 revious studies showed the colocalization of KIT with DAPI-stained nuclei in GIST cells without knowi

186 ve microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted

187 To investigate the effect of KIT and PDGFRA mutations on recurrence-free survival (RF

188 However, some GISTs lose expression of KIT oncoproteins, and therefore become KIT-independent a

189 of ets variant 1 and increased expression of KIT, causing rapid GE.

190 mutant cancer, particularly after failure of KIT TKIs.

191 Conversely, an increase of KIT levels augments, but a reduction of KIT expression a

192 ver differences in the immune infiltrates of KIT and PDGFRA-mutant GIST.

193 inib is a well-tolerated, novel inhibitor of KIT and PDGFRA mutant kinases with promising activity in

194 Resistance to approved inhibitors of KIT proto-oncogene, receptor tyrosine kinase (KIT), and

195 n and RNA interference-mediated knockdown of KIT reduced expression of CCL2.

196 lele ratios were associated with the lack of KIT or FLT3 mutations and a favorable outcome.

197 these melanomas exhibit a surprising loss of KIT expression, which raises the question of whether los

198 which raises the question of whether loss of KIT in these tumors facilitates tumorigenesis.

199 tein-dependent, whereas sublines had loss of KIT oncoprotein expression, accompanied by markedly down

200 ve in GIST cells through a dual mechanism of KIT transcriptional downregulation and upregulation of t

201 or midostaurin has validated the paradigm of KIT inhibition in advSM, and the efficacy and safety of

202 Moreover, presence of KIT-mutated MSCs was associated with more advanced disea

203 To overcome the problem of KIT TKI resistance, we sought to identify novel therapeu

204 Moreover, suppressing production of KIT-ligand in Sca1(+) progenitors inhibits their ability

205 We observed increased proportions of KIT(+) ILC2s among patients with mastocytosis, regardles

206 nhibitor designed to inhibit a wide range of KIT and PDGFRA mutations.

207 ept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs.

208 that LMTK3 regulated the translation rate of KIT, such that loss of LMTK3 reduced total KIT, and thus

209 univariate analyses at month 6, reduction of KIT D816V EAB >/=25%, tryptase >/=50%, and alkaline phos

210 e of KIT levels augments, but a reduction of KIT expression ablates DNMT1 transcription by STAT3 path

211 on therapy to overcome imatinib-resistant of KIT-expressing GISTs.

212 ib influences the prognostic significance of KIT proto-oncogene receptor tyrosine kinase (KIT) and pl

213 inhibitor active against a broad spectrum of KIT and PDGFRA mutations, with placebo in patients with

214 osine in the prophase nucleus of a subset of KIT(+) progenitors during mitosis.

215 Targeting of KIT and PDGFRA with imatinib revolutionised treatment in

216 The treatment of KIT-mutant GIST has been revolutionized with the advent

217 espite clinical advances in the treatment of KIT/PDGFRA-mutant GIST, similar progress against KIT/PDG

218 sitively correlated with the upregulation of KIT in tumor tissues.

219 acking the SRC family kinase-binding site on KIT (pY567) exhibited attenuated MAPK signaling and tumo

220 abrogating specific phosphorylation sites on KIT.

221 The proto-oncogene KIT encodes for a tyrosine kinase receptor, which is a c

222 Oncogenic KIT or PDGFRA tyrosine kinase mutations are compelling t

223 romal tumors (GISTs) are driven by oncogenic KIT signaling and can therefore be effectively treated w

224 eating cancers driven by all known oncogenic KIT mutants.

225 In multivariate analysis, only KIT D816V EAB reduction >/=25% remained an independent o

226 sified as KIT responders (>/=25%, n = 17) or KIT nonresponders (<25%, n = 11).

227 While the deregulated activation of DNMT1 or KIT has been implicated in lung cancer pathogenesis, whe

228 n was extremely low in two of three parental KIT-dependent GIST lines, whereas cyclin D1 expression w

229 rimary and secondary mutations of pathogenic KIT/PDGFRA oncoproteins.

230 er mean expression levels of nuclear phospho-KIT and NFKBIB as compared with those of intermediate or

231 kinase mast/stem cell growth factor receptor KIT is an example of a clinically relevant RTK.

232 FcepsilonRI]), the stem cell factor receptor KIT, the IL-4 system, and both Ca(2+)- and phosphatase-d

233 Stem cell factor and its receptor, KIT, are central to mast-cell homeostasis.

234 Sensitive detection of the recurrent KIT D816V mutation and use of next-generation sequencing

235 ation of the KIT enhancer domain and reduced KIT gene expression.

236 alproic acid, treatment to result in reduced KIT expression and relative cell viability of imatinib-r

237 KIT promoter region and subsequently reduced KIT transcription/expression and the viability of GIST c

238 xistence of a nuclear KIT-driven NFKBIB-RELA-KIT autoregulatory loop in GIST tumorigenesis, which are

239 in which the heterogeneity of drug-resistant KIT mutations is a major challenge.

240 lines tested, even those with drug-resistant KIT secondary mutations.

241 of activity due to drug-resistant secondary KIT mutations that arise (or that are selected for) duri

242 evelop imatinib resistance through secondary KIT mutations.

243 Sensitive KIT D816V mutation analysis of blood has been proposed t

244 The outcome of sensitive KIT D816V analysis of blood was compared to the result o

245 d subsets of melanoma, are caused by somatic KIT mutations that result in KIT receptor tyrosine kinas

246 one marrow (BM) hematopoiesis by the somatic KIT D816V mutation is present in a subset of adult indol

247 risk of GIST recurrence associated with some KIT mutations, including deletions that affect exon 11 c

248 hese enriched SSCs with differentiating SPG (KIT(+) cells) revealed the full complement of genes that

249 prognostic factors, only performance status, KIT mutation, and size of largest lesion predicted long-

250 herefore, therapeutic strategies that target KIT independently of the mutational status are intriguin

251 Ripretinib inhibits all tested KIT and PDGFRA mutants, and notably is a type II kinase

252 Mutations in genes other than KIT frequently found in myeloid neoplasms have been asso

253 We provided evidence that KIT inactivation induces global DNA hypomethylation, res

254 Here we show that KIT D816V promotes expression of the proangiogenic cytok

255 Together, these results suggest that KIT can activate signaling through wild-type RAF protein

256 These results suggest that KIT-dependent processes and mast cells contribute to the

257 The KIT mutation was a significant factor predicting a lower

258 The KIT promoter contains a G-rich domain within a relativel

259 ents with mutated MSCs may have acquired the KIT mutation in a common pluripotent progenitor cell, pr

260 rointestinal stromal tumors (GISTs), and the KIT inhibitor, imatinib, is therefore standard of care f

261 l stem cells (MSCs) from ISM patients by the KIT D816V mutation and its potential impact on disease p

262 Correspondingly, the KIT-targeting drug midostaurin and RNA interference-medi

263 ASqPCR for the KIT D816V mutation was a useful adjunct in helping ident

264 e-specific quantitative PCR (ASqPCR) for the KIT D816V mutation, and a bone marrow examination.

265 haracterized by an oncogenic mutation in the KIT or platelet-derived growth factor receptor alpha (PD

266 ) is driven by an activating mutation in the KIT proto-oncogene.

267 Ts are caused by activating mutations in the KIT receptor tyrosine kinase, such as the exon 11 KIT V5

268 because of gain-of-function mutations in the KIT receptor.

269 only 10 (30%) of 33 patients, including the KIT D816V (n = 5), K509I (n = 3), N819Y (n = 1), and I81

270 cond recurrent insulator loss event near the KIT oncogene, which is also highly expressed across SDH-

271 Depending on the relative reduction of the KIT D816V expressed allele burden (EAB) at month 6, pati

272 (advSM) is characterized by presence of the KIT D816V mutation and pathologic accumulation of neopla

273 n GIST cells arising from attenuation of the KIT enhancer domain and reduced KIT gene expression.

274 study, we identify regulatory regions of the KIT enhancer essential for KIT gene expression and GIST

275 dentification of activating mutations of the KIT gene in gastrointestinal stromal tumor (GIST)-the mo

276 ed a 42-base pair deletion in exon 11 of the KIT gene that would delete all or part of codons 558 to

277 a clinical point of view, acquisition of the KIT mutation in an earlier BM precursor cell confers a s

278 f, or highly suspected SM, regardless of the KIT mutation status.

279 t the structural and functional study of the KIT promoter core sequence, in both single- and double-s

280 cyclin D1 expression was high in each of the KIT-independent GIST sublines.

281 nuclear translocation that could bind to the KIT promoter region and subsequently reduced KIT transcr

282 at loss of LMTK3 reduced total KIT, and thus KIT downstream signaling in cancer cells.

283 significantly higher level when compared to KIT-mutant GISTs and exhibited more diverse driver-deriv

284 ncreased cytolytic activity when compared to KIT-mutant GISTs.

285 nd that nuclear factor kappaB contributes to KIT-dependent upregulation of CCL2 in mast cells.

286 ndependent and are consequently resistant to KIT-inhibitor drugs.

287 ted, mutant KIT and have durable response to KIT tyrosine kinase inhibitor.

288 Biologic mechanisms unique to KIT-independent GISTs were identified by transcriptome s

289 f KIT, such that loss of LMTK3 reduced total KIT, and thus KIT downstream signaling in cancer cells.

290 ons were suggested by studies in traditional KIT mutant MC-deficient mouse strains.

291 LC-associated IL7R (CD127), TNFSF10 (TRAIL), KIT (CD117), IL2RA (CD25), CD27, CXCR3, DPP4 (CD26), GPR

292 No significant changes in s-tryptase/KIT D816V allele burden were observed.

293 GIST lines in which the parental forms were KIT oncoprotein-dependent, whereas sublines had loss of

294 were associated with favorable RFS, whereas KIT exon 9 mutations were associated with unfavorable ou

295 unrecognized clonal mast cell disorders with KIT mutations may present as Hymenoptera-induced or idio

296 nal stromal tumours, including patients with KIT and PDGFRA D842V-mutant gastrointestinal stromal tum

297 Patients with KIT exon 11 deletion mutations benefit most from the lon

298 Patients with KIT exon 11 deletion or insertion-deletion mutation had

299 3 as a target for treatment of patients with KIT-mutant cancer, particularly after failure of KIT TKI

300 Similarly, in the subset with KIT exon 11 deletion mutations, higher-than-the-median m