ライフサイエンスコーパス: FLT3

1 lly to combinatorial inhibition of FGFR1 and FLT3.

2 AML results in resistance to drugs targeting FLT3.

3 n KRAS, NRAS or the receptor tyrosine kinase FLT3.

4 3) as well as a potent activity at a kinase, FLT3.

5 3/ITD AML cells with selective inhibitors of FLT3.

6 icated common and rare germ-line variants at FLT3 (a gene often somatically mutated in leukemia) asso

7 with previously untreated AML and confirmed FLT3-activating mutations, mostly younger than 60 years,

8 ver, sorafenib treatment effectively blocked FLT3 activation in resistant cells, whereas it was unabl

9 th acute myeloid leukemia (AML), which makes FLT3 an attractive target for the treatment of AML.

10 -ITD on dendritic cells (DCs), which express FLT3 and can be expanded by FLT3L administration.

11 New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, K

12 ML) treatment: targeted therapies for mutant FLT3 and IDH2, a liposomal cytarabine-daunorubicin formu

13 hat constitutive signaling driven by mutated FLT3 and JAK2 confers interchromosomal homologous recomb

14 ted in derepression of the oncogenic kinases FLT3 and JAK2, leading to enhanced ERK and STAT3 signali

15 Thus, concomitant targeting of FLT3 and MAPK may potentially exert synergistic activity

16 e cells were treated with inhibitors of both FLT3 and MEK in combination, ERK reactivation was abroga

17 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC path

18 omolog CDK4 is found at the promoters of the FLT3 and PIM1 genes, another important leukemogenic driv

19 of secondary resistance via reactivation of FLT3 and RAS/MAPK signaling.

20 id leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic featur

21 ctivity against the receptor tyrosine kinase FLT3, and its approval will hopefully mark the beginning

22 c kinase pathway inhibitors to perturb ABL1, FLT3, and JAK TK signaling in four xenografted patient s

23 Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are assoc

24 ing mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and dri

25 approaches and newly created reporter mice (Flt3-BFP2, Mertk-GFP-DTR, Cd4-tdTomato, Cd8a-tdTomato),

26 tion of resistant secondary mutations at the FLT3 catalytic domain, which is mainly on D835.

27 n of numerous mutations, including Apc, Nf1, Flt3, Cbl, Notch1 and Mll2, which are recurrently delete

28 Indeed, Sfpi1(+/-) mice had reduced Flt3(+)CD11c(-)MHCII(+) monocytes and GM-CSF-dependent F

29 R4A1- and Flt3L-independent, CCR2-dependent, Flt3(+)CD11c(-)MHCII(+)PU.1(hi) subset.

30 By contrast, Flt3(-)CD11c(-)MHCII(-)PU.1(lo) monocytes differentiated

31 mphoid genes are expressed by MPP3 cells and Flt3(-) CLPs, the latter only give rise to B cells in th

32 FL directly attenuated AC220 inhibition of FLT3, consistent with previous reports.

33 dritic cell-associated genes, including CD1, FLT3, CX3CR1, and CCR6 Each clade, and each member of bo

34 el FLT3 inhibitor, which selectively targets FLT3 D835 mutants as well as FLT3-ITD.

35 sting that the resistant cells are no longer FLT3 dependent.

36 ably distinguish FLT3-independent moDCs from FLT3-dependent cDCs in C57BL/6 mice.

37 In this article, we report that Flt3-derived dendritic cells from these mice overproduce

38 enefit of adding FMS-like tyrosine kinase-3 (FLT3)-directed small molecule therapy to standard first-

39 inhibition encourage continued evaluation of FLT3-directed therapy alongside front-line AML treatment

40 s, IB was highly effective at killing mutant FLT3-driven AML cells through a similar mechanism as tha

41 ated the antileukemia activity of a MEK1 and FLT3 dual inhibitor, E6201, in AML cells resistant to FL

42 high GFI1 expression is paralleled by higher FLT3 expression, and, even when the FLT3 gene is not mut

43 iHR activity in internal tandem duplication FLT3 (FLT3-ITD) and JAK2V617F-mutated cells.

44 y higher FLT3 expression, and, even when the FLT3 gene is not mutated, exhibit a FLT3-ITD signature o

45 tivity of multiple kinases, including AURKA, FLT3, GSK3A, MAP3K, MEK, RSK2, RSK4, PLK4, ULK1, and JAK

46 Therapy directed against oncogenic FLT3 has been shown to induce response in patients with

47 kinase fms-like tyrosine kinase 3 receptor (Flt3) has an important role during early B-cell developm

48 Inhibitors to FLT3 have already been tested in clinical trials, howeve

49 Fzd6 deficiency increased the ratio of Flt3(hi) multipotent progenitors to CD150(+) stem cells

50 nitors (LMPPs) (Lin(-)Sca-1(+)c-Kit(+)CD34(+)Flt3(hi)) and common myeloid progenitors (CMPs) (Lin(-)S

51 tated alleles, including a mutation encoding FLT3(I836M) that was called in four cases.

52 kemia, we identified a MEGS with five genes (FLT3, IDH2, NRAS, KIT, and TP53) and a MEGS (NPM1, TP53,

53 ng early B-cell development, but the role of Flt3 in peripheral B cells has not been assessed before.

54 y did not identify any acquired mutations in FLT3 in the resistant cells.

55 ay of CD88 and CD26 can reliably distinguish FLT3-independent moDCs from FLT3-dependent cDCs in C57BL

56 Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppres

57 In the search for compounds with broad FLT3 inhibition activities, we screened a kinase inhibit

58 ation of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in

59 elative studies included analysis of in vivo FLT3 inhibition by plasma inhibitory activity assay and

60 Moreover, FLT3 inhibition elicited severe mitochondrial oxidative

61 utcomes seen in patients achieving sustained FLT3 inhibition encourage continued evaluation of FLT3-d

62 ansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic

63 ourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory

64 ents who achieved sustained greater than 85% FLT3 inhibition.

65 inhibitor, E6201, in AML cells resistant to FLT3 inhibition.

66 anism that promotes AML cell survival during FLT3 inhibition.

67 Fms-like tyrosine kinase 3 (FLT3) inhibition has elicited encouraging responses in a

68 drial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vit

69 We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or

70 dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis.

71 ts, which facilitated evaluation of the JAK2/FLT3 inhibitor pacritinib in vivo.

72 acophore merging strategy combining the JAK2/FLT3 inhibitor pacritnib with the pan-HDAC inhibitor, vo

73 ns at the time of acquired resistance to the FLT3 inhibitor quizartinib.

74 in the FLT3 kinase domain that contribute to FLT3 inhibitor resistance, MEK/ERK signaling is persiste

75 To address the mechanism of FLT3 inhibitor resistance, we generated two resistant AM

76 L cell lines by sustained treatment with the FLT3 inhibitor sorafenib.

77 asia mutated) as being synthetic lethal with FLT3 inhibitor therapy.

78 tor VI (designated JI6 hereafter) as a novel FLT3 inhibitor, which selectively targets FLT3 D835 muta

79 bone marrow signaling may be upregulated in FLT3 inhibitor-resistant AML with secondary kinase domai

80 inhibitor and fms-related tyrosine kinase 3 (FLT3) inhibitor as single agents and in combination.

81 FLT3 inhibitors are being developed as targeted therapy

82 Although FLT3 inhibitors have shown considerable promise for the

83 The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia

84 While FLT3 inhibitors like sorafenib show initial therapeutic

85 nce, combined treatment with palbociclib and FLT3 inhibitors results in synergistic cytotoxicity.

86 ough FLT3-mutant patients respond to current FLT3 inhibitors, relapse usually happens because of the

87 Potent FLT3 inhibitors, such as quizartinib (AC220), have shown

88 s that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interfer

89 ation) mutation and are highly responsive to FLT3 inhibitors, whereas resistant cell lines display re

90 plete remission and overcoming resistance to FLT3 inhibitors.

91 nt cell lines display resistance to multiple FLT3 inhibitors.

92 ying degrees of resistance to the individual FLT3 inhibitors.

93 enhance current therapeutic approaches using FLT3 inhibitors.

94 Ascorbate depletion cooperated with Flt3 internal tandem duplication (Flt3(ITD)) leukaemic m

95 The FLT3 Internal Tandem Duplication (FLT3(ITD)) mutation is

96 FLT3 internal tandem duplication (FLT3-ITD) is an activa

97 ting acute myeloid leukemia (AML) containing FLT3 internal tandem duplication (ITD) mutations.

98 we show that DNMT3A loss synergizes with the FLT3 internal tandem duplication in a dose-influenced fa

99 loid leukemia (AML) patients with activating FLT3 internal tandem duplication mutations at the time o

100 or absence of NPM1 mutations (NPM1(mut)) and FLT3 internal tandem duplications (FLT3-ITD).

101 leukemia (AML) and frequently co-occur with FLT3 internal tandem duplications (ITD) or, less commonl

102 luding difficult-to-detect mutations such as FLT3 internal-tandem and mixed-lineage leukemia (MLL) pa

103 of the Fms-like tyrosine kinase-3 receptor (FLT3) internal tandem duplication (ITD) is found in 30%

104 ulated by mutant Fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD), which mediate r

105 cute myeloid leukemia (AML) that harbors the FLT3-internal tandem duplication (FLT3-ITD) mutation.

106 ysis, an abnormal karyotype, the presence of FLT3-internal tandem duplication (ITD), and a < 4-log re

107 sive consolidation within the cytogenetic or FLT3-internal tandem duplication and NPM1 gene mutation

108 were balanced for age, karyotypic risk, and FLT3-internal tandem duplication and NPM1 gene mutations

109 of AML cells that possess an M5 subtype with FLT3-internal tandem duplication mutation.

110 ed between lestaurtinib and control: 74% had FLT3-internal tandem duplication mutations, 23% FLT3-tyr

111 kemia (AML) harboring NPM1 mutations without FLT3-internal tandem duplications (ITDs; NPM1-positive/F

112 We hypothesized that FLT3/internal tandem duplication (ITD) leukemia cells ex

113 of combining ATRA and FLT3 TKIs to eliminate FLT3/internal tandem duplication (ITD)(+) LSCs.

114 These findings confirm that FLT3 is a high-value target for treatment of relapsed or

115 FLT3 is a trans-membrane receptor with a tyrosine kinase

116 We show that Flt3 is reexpressed on B-cell lymphoma 6(+) germinal cen

117 addiction to the Fms-like tyrosine kinase 3 (FLT3) is a hallmark of acute myeloid leukemia (AML) that

118 altered gene expression profile in Npm1(cA);Flt3(ITD) , but not Npm1(cA/+);Nras(G12D/+) , progenitor

119 Here we show that Flt3(ITD) and cooperating Flt3(ITD)/Runx1 mutations caus

120 Cooperative interactions between Flt3(ITD) and Runx1 mutations are also blunted in fetal/

121 While FLT3(ITD) can activate STAT5 signal transduction prior t

122 Pre-leukemic mice with the Flt3(ITD) knock-in allele manifested an expansion of cla

123 Flt3(ITD) mice showed enhanced capacity to support T cel

124 However, Npm1(cA);Flt3(ITD) mutants displayed significantly higher periphe

125 Flt3(ITD) mutations and Tet2 loss cooperatively remodele

126 compound Npm1(cA/+);Nras(G12D/+) or Npm1(cA);Flt3(ITD) share a number of features: Hox gene overexpre

127 In adult progenitors, FLT3(ITD) simultaneously induces self-renewal and myeloi

128 on because they are not competent to express FLT3(ITD) target genes.

129 ions in the FMS-like tyrosine kinase 3 gene (Flt3(ITD)) and the nucleophosmin gene (Npm1(c)) to induc

130 rated with Flt3 internal tandem duplication (Flt3(ITD)) leukaemic mutations to accelerate leukaemogen

131 The FLT3 Internal Tandem Duplication (FLT3(ITD)) mutation is common in adult acute myeloid leu

132 Here we show that Flt3(ITD) and cooperating Flt3(ITD)/Runx1 mutations cause hematopoietic stem cell

133 cell intrinsic, and was further enhanced in Flt3(ITD/ITD) mice.

134 Patients with FLT3-ITD (24%),DNMT3A(24%), and NPM1(26%) mutant AML all

135 Parental cell lines carry the FLT3-ITD (tandem duplication) mutation and are highly re

136 itivity is strongly correlated with a higher FLT3-ITD allelic burden.

137 nt, and < 4-log reduction in PB-MRD, but not FLT3-ITD allelic ratio, remained of significant prognost

138 FLT3-ITD AML patients treated with AC220 developed incre

139 reverses the cyto-protective role of BMSC on FLT3-ITD AML survival.

140 ar FGF2, to improve the depth of response in FLT3-ITD AML.

141 lation and confirmed high HHEX expression in FLT3-ITD AMLs.

142 STAT5 activation, and combined targeting of FLT3-ITD and BTK showed additive effects.

143 4-11 cells and HCD-57 cells transformed with FLT3-ITD and D835 mutants.

144 Our findings show that mutated FLT3-ITD and JAK2 augment ROS production and HR, shiftin

145 c strategies that modulate the expression of FLT3-ITD are also promising.

146 Co-occurrence of mutant NPM1 with FLT3-ITD carries a significantly worse prognosis than NP

147 dox, we investigated the impact of RUNX1 and FLT3-ITD coexpression.

148 Cells expressing mutated FLT3-ITD demonstrated a relative increase in mutation fr

149 FLT3-ITD directly impacts on RUNX1 activity, whereby up-

150 AML patient samples with FLT3-ITD express high levels of RUNX1, a transcription f

151 LC3 prevented AML cell death in response to FLT3-ITD inhibition by crenolanib, which was restored by

152 tional genomic screening, we determined that FLT3-ITD is a biomarker of response to MTHFD2 suppressio

153 pressed the myeloproliferative phenotypes in FLT3-ITD knock-in mice, and significantly prolonged the

154 e inhibitor palbociclib induces apoptosis of FLT3-ITD leukemic cells.

155 We hypothesize that this effect of FLT3-ITD might subvert immunosurveillance and promote le

156 FLT3-ITD molecules were detectable within autophagosomes

157 Thus, the FLT3-ITD mutation directly affects DC development, indir

158 We show that AML samples bearing FLT3-ITD mutations are more sensitive to proteasome inhi

159 Therefore, selecting patients according to FLT3-ITD mutations could be a new way to detect a signif

160 Increased HR activity in G0 arrested primary FLT3-ITD NK-AML in contrast to wild-type FLT3 NK-AML.

161 f iHR, was significantly elevated in primary FLT3-ITD normal karyotype acute myeloid leukemia (NK-AML

162 We analyzed the effect of FLT3-ITD on dendritic cells (DCs), which express FLT3 an

163 oup of older patients (50-60 years) with the FLT3-ITD or NPM1 mutation.

164 Constitutively active FLT3-ITD promotes the expansion of transformed progenito

165 nduction of autophagy in vivo, downregulated FLT3-ITD protein expression and improved overall surviva

166 Molecular or pharmacologic inhibition of FLT3-ITD reactivated ceramide synthesis, selectively ind

167 Moreover, activating FLT3-ITD signaling in crenolanib-resistant AML cells sup

168 h lipid ceramide generation is suppressed by FLT3-ITD signaling.

169 NA and protein and to the down regulation of FLT3-ITD signature genes, thus linking two major prognos

170 when the FLT3 gene is not mutated, exhibit a FLT3-ITD signature of gene expression.

171 ntified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression

172 Mechanistically, FLT3-ITD targeting induced ceramide accumulation on the

173 nd lethal mitophagy induction in response to FLT3-ITD targeting was mediated by dynamin-related prote

174 ceramide-dependent mitophagy in response to FLT3-ITD targeting.

175 ted and phosphorylated RUNX1 cooperates with FLT3-ITD to induce AML.

176 HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML.

177 enhanced HSC self-renewal or cooperate with Flt3-ITD to induce myeloid transformation.

178 r data reveal that miR-155 collaborates with FLT3-ITD to promote myeloid cell expansion in vivo and t

179 cantly worse prognosis associated with NPM1c/FLT3-ITD vs NPM1/NRAS-G12D-mutant AML and functionally c

180 FLT3-ITD(+) acute myeloid leukemia (AML) accounts for ap

181 are being developed as targeted therapy for FLT3-ITD(+) acute myeloid leukemia; however, their use i

182 Further, inhibition of miR-155 in FLT3-ITD(+) AML cell lines using CRISPR/Cas9, or primary

183 n and mitophagy in response to crenolanib in FLT3-ITD(+) AML cells expressing stable shRNA against en

184 T3-WT) AML and is critical for the growth of FLT3-ITD(+) AML cells in vitro.

185 stent with our observations in mice, primary FLT3-ITD(+) AML clinical samples have significantly high

186 5 (miR-155) is specifically overexpressed in FLT3-ITD(+) AML compared with FLT3 wild-type (FLT3-WT) A

187 FLT3-ITD(+) AML drug resistance is attenuated by LCL-461

188 AML cell lines using CRISPR/Cas9, or primary FLT3-ITD(+) AML samples using locked nucleic acid antise

189 ctivity in internal tandem duplication FLT3 (FLT3-ITD) and JAK2V617F-mutated cells.

190 FLT3 internal tandem duplication (FLT3-ITD) is an activating mutation found in 20-30% of p

191 arbors the FLT3-internal tandem duplication (FLT3-ITD) mutation.

192 3 mutation, the internal tandem duplication (FLT3-ITD) mutation.

193 duplication of the FMS-like tyrosine kinase (FLT3-ITD) receptor is present in 20% of acute myeloid le

194 rosine kinase 3 internal tandem duplication (FLT3-ITD)-positive AML, BTK mediates FLT3-ITD-dependent

195 mut)) and FLT3 internal tandem duplications (FLT3-ITD).

196 Functional studies in human FLT3-ITD+ cell lines showed that BMX is part of a compen

197 nd fibroblast growth factor 2 (FGF2) protect FLT3-ITD+ MOLM14 cells from AC220, providing time for su

198 ated in an in vivo murine FLT3-ITD-positive (FLT3-ITD+) model of sorafenib resistance.

199 1q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations.

200 NPM1 mutations in the absence of FLT3-ITD, mutated TP53, and biallelic CEBPA mutations we

201 In the subset of patients with FLT3-ITD, only age, white blood cell count, and < 4-log

202 was responsible for the early degradation of FLT3-ITD, which preceded the inhibition of mitogen-activ

203 Treatment of FLT3-ITD- and JAK2V617F-mutant cells with the antioxidan

204 JI6 effectively inhibited FLT3-ITD-containing MV4-11 cells and HCD-57 cells transf

205 rrant activation of the PI3K/mTOR pathway in FLT3-ITD-dependent AML results in resistance to drugs ta

206 cation (FLT3-ITD)-positive AML, BTK mediates FLT3-ITD-dependent Myc and STAT5 activation, and combine

207 Results indicate that miR-155 promotes FLT3-ITD-induced myeloid expansion in the bone marrow, s

208 hether miR-155 influences the development of FLT3-ITD-induced myeloproliferative disease.

209 However, miR-155's role in regulating FLT3-ITD-mediated disease in vivo remains unclear.

210 In multivariable analysis, NPM1-positive/FLT3-ITD-negative genotype remained independently associ

211 NPM1-positive/FLT3-ITD-negative genotype remains a relatively favorabl

212 nal tandem duplications (ITDs; NPM1-positive/FLT3-ITD-negative genotype) are classified as better ris

213 ation was recapitulated in an in vivo murine FLT3-ITD-positive (FLT3-ITD+) model of sorafenib resista

214 ctively targets FLT3 D835 mutants as well as FLT3-ITD.

215 ignaling within hours following treatment of FLT3/ITD AML cells with selective inhibitors of FLT3.

216 potently inhibited survival of primary human FLT3/ITD(+) AML cells compared to FLT3/ITD(neg) cells an

217 tivity, preferentially inducing apoptosis in FLT3/ITD(+) cell lines and patient samples.

218 rther demonstrate decreased clonogenicity of FLT3/ITD(+) cells upon treatment with ATRA and TKI.

219 ential of this drug combination to eliminate FLT3/ITD(+) LSCs and reduce the rate of relapse in AML p

220 t importantly, the drug combination depletes FLT3/ITD(+) LSCs in a genetic mouse model of AML, and pr

221 Furthermore, engraftment of primary FLT3/ITD(+) patient samples is reduced in mice following

222 mary human FLT3/ITD(+) AML cells compared to FLT3/ITD(neg) cells and spared normal umbilical cord blo

223 dentified the highest percentage of reported FLT3-ITDs when compared to other ITD detection algorithm

224 ition to the acquired point mutations in the FLT3 kinase domain that contribute to FLT3 inhibitor res

225 lgorithms, and discovered additional ITDs in FLT3, KIT, CEBPA, WT1 and other genes.

226 hereby extrinsic microenvironmental proteins FLT3 ligand (FL) and fibroblast growth factor 2 (FGF2) p

227 Flt3 ligand (Flt3L) promotes survival of lymphoid progen

228 ion (ITD) in FLT3, the receptor for cytokine FLT3 ligand (FLT3L).

229 Finally, postsepsis Flt3 ligand treatment increased the number of DCs and im

230 orted exponential growth of L. monocytogenes Flt3 ligand-induced cultures yielded CD103(+)CD11c(+) ce

231 Fms-like tyrosine kinase-3 (Flt3) ligand (FL) and Interleukin-7 (IL-7) are cytokines

232 ound that the Lin(-)CD34(+)CD38(mid)CD45RA(-)FLT3(-)MPL(+)CD36(-)CD41(-) population is much more high

233 he 120 mg and 200 mg dose cohorts to include FLT3(mut+) patients only.

234 ients with locally confirmed FLT3 mutations (FLT3(mut+)) to be enrolled in expansion cohorts at each

235 FMS-like tyrosine kinase 3 (FLT3)-mutant acute myeloid leukemia (AML) portends a poo

236 and Drug Administration for the treatment of FLT3-mutant acute myeloid leukemia (AML).

237 The effect is specific for FLT3-mutant cells and is ascribed to the transcriptional

238 Although FLT3-mutant patients respond to current FLT3 inhibitors,

239 eutic strategy for the improved treatment of FLT3 mutated AML.

240 FLT3-mutated acute myeloid leukemia (AML), despite not b

241 and improved the survival of mice in a human FLT3-mutated AML model.

242 ble in younger patients with newly diagnosed FLT3-mutated AML, but yielded no overall clinical benefi

243 inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong o

244 ents with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes.

245 Although the presence of an FLT3 mutation was not an inclusion criterion, we require

246 e patients harboring the most common type of FLT3 mutation, the internal tandem duplication (FLT3-ITD

247 -free survival among patients with AML and a FLT3 mutation.

248 ation was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase dom

249 ten or more patients with locally confirmed FLT3 mutations (FLT3(mut+)) to be enrolled in expansion

250 tios were associated with the lack of KIT or FLT3 mutations and a favorable outcome.

251 Whether or not FLT3 mutations are present and expressed within a leukem

252 For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3

253 valuation of E6201 in AML patients harboring FLT3 mutations, including those who relapse following FL

254 on AML cells harboring resistance-conferring FLT3 mutations.

255 uce the rate of relapse in AML patients with FLT3 mutations.

256 in human AML blasts with clinically relevant FLT3 mutations.

257 ears of age, who had newly diagnosed AML for FLT3 mutations.

258 ary FLT3-ITD NK-AML in contrast to wild-type FLT3 NK-AML.

259 id leukemia (NK-AML) compared with wild-type FLT3 NK-AML.

260 o) 2 patients] were identified for 10 genes (FLT3, NRAS, PTPN11, WT1, TET2, DHX15, DHX30, KIT, ETV6,

261 IL7R, SH2B3, JAK1) in 6.3% or other kinases (FLT3, NTRK3, LYN) in 4.6%, and mutations involving the R

262 The mutation caused the down-regulation of Flt3 on the surface of DCs and reduced their responsiven

263 comes may be observed with rearrangements of FLT3 or ABL1 (eg, both of which commonly partner with ET

264 els acquired additional copies of the mutant Flt3 or Nras alleles, but only Npm1(cA/+);Nras(G12D/+) m

265 most pronounced in patient samples harboring FLT3 or PDGFRB alterations.

266 At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in mos

267 ersistently activated in AML cells even when FLT3 phosphorylation is continually suppressed.

268 In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels.

269 n exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentra

270 ry of the LSK-CD48(-)CD150(+) and LSK-CD34(-)Flt3(-) populations 15 to 18 months after Moz deletion.

271 on of the LSK-CD48(-)CD150(+) and LSK-CD34(-)Flt3(-) populations in the bone marrow and a reduction i

272 emia (sAML; in comparison to high-risk MDS), FLT3, PTPN11, WT1, IDH1, NPM1, IDH2 and NRAS mutations (

273 s involving NPM1 or signaling molecules (eg, FLT3, RAS) typically are secondary events that occur lat

274 Internal tandem duplications (ITDs) in the FLT3 receptor tyrosine kinase are common mutations in AM

275 g internal tandem duplications (ITDs) of the FLT3 receptor tyrosine kinase.

276 cell line led to a decrease in the level of FLT3 RNA and protein and to the down regulation of FLT3-

277 , administration of JI6 effectively targeted FLT3 signaling in vivo and suppressed the myeloprolifera

278 kinase inhibitor library by using our unique FLT3 substrate and identified JAK3 inhibitor VI (designa

279 The FLT3 subtype was ITD (high) in 214 patients, ITD (low) i

280 ere well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not

281 fit of midostaurin was consistent across all FLT3 subtypes.

282 induced by mutations in the kinase domain of FLT3, suggesting that these compounds may prevent the em

283 tions, including those who relapse following FLT3-targeted monotherapy.

284 to counteract the resistance of AML cells to FLT3-targeted therapy.

285 is the internal tandem duplication (ITD) in FLT3, the receptor for cytokine FLT3 ligand (FLT3L).

286 is reduced in mice following treatment with FLT3 TKI and ATRA in combination, with evidence of cellu

287 at least in part due to the observation that FLT3 TKI treatment upregulates the antiapoptotic protein

288 vide evidence that the synergism of ATRA and FLT3 TKIs is at least in part due to the observation tha

289 explored the efficacy of combining ATRA and FLT3 TKIs to eliminate FLT3/internal tandem duplication

290 FLT3 tyrosine kinase inhibitors (TKIs) used as monothera

291 FMS-like tyrosine kinase-3 (FLT3) tyrosine kinase inhibitors (TKI) have been tested

292 ling axis, connecting genetic aberrations in FLT3, tyrosine kinase 2 (TYK2), platelet-derived growth

293 3-internal tandem duplication mutations, 23% FLT3-tyrosine kinase domain point mutations, and 2% both

294 The common FLT3 variant rs76428106 has a large allele frequency dif

295 kinase signaling (including KIT, N/KRAS, and FLT3) were frequent in both subtypes of CBF-AML.

296 erexpressed in FLT3-ITD(+) AML compared with FLT3 wild-type (FLT3-WT) AML and is critical for the gro

297 he intermediate risk genotype NPM1 wild-type/FLT3 without internal-tandem duplications (EFS, 18% +/-

298 is of CEBPalpha among patients with NPM1(wt)/FLT3(wt) revealed excellent results both in patients wit

299 evels and a lower IFN response compared with FLT3-WT AML samples.

300 LT3-ITD(+) AML compared with FLT3 wild-type (FLT3-WT) AML and is critical for the growth of FLT3-ITD(