ライフサイエンスコーパス: FLT3

1 ing mutation in the receptor tyrosine kinase FLT3.

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

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

4 associating domain border and an enhancer of FLT3.

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

6 targeting FLT3, our team engineered an alpha-FLT3-A192 fusion protein composed of a single chain vari

7 In conclusion, alpha-FLT3-A192 fusions appear to be a viable new modality for

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

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

10 locus, which results in higher expression of FLT3, an important driver gene in acute leukemias.

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

12 emonstrated that 9u inhibited phosphorylated FLT3 and downstream signaling factors and also induced c

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

14 he 13q12.2 deletions occur immediately 5' of FLT3 and involve the PAN3 locus.

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

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

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

18 icantly superior reduction of phosphorylated FLT3 and transcriptional suppression of genes downstream

19 ions in FMS-like tyrosine kinase receptor-3 (FLT3) and Nucleophosmin-1 (NPM1) are most frequent alter

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

21 ma 2, midostaurin and gilteritinib to target FLT3, and ivosidenib and enasidenib to target mutant iso

22 3 tyrosine kinase inhibitors (TKIs) and anti-FLT3 antibodies, have demonstrated promising preclinical

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

24 sine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutated in acute myeloid leukemia

25 These results indicate that abolishing FLT3 arginine methylation through PRMT1 inhibition repre

26 These data further emphasize the role of FLT3 as a driver gene in BCP ALL.

27 hylates Fms-like receptor tyrosine kinase 3 (FLT3) at arginine (R) residues 972 and 973 (R972/973), a

28 n factor and its transcriptional target gene FLT3 being the most pronounced.

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

30 l for cytokine receptor signaling (including FLT3), by the small molecule allosteric inhibitor SHP099

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

32 In one MS-RO+ LCH patient, CD34+c-Kit+Flt3+ cell frequency in blood and its BRAF-mutated offsp

33 CD34+c-Kit+Flt3+ cells from BM of MS-RO+ LCH patients produced Lang

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

35 (BSc5371) displays superior cytotoxicity in FLT3-dependent cell lines to compounds in recent clinica

36 clear cells (PBMCs) and synergistic in human FLT3-differentiated mBMDCs and CAL-1 pDCs.

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

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

39 FLT3, DNMT3A, and NPM1 are the most frequently mutated g

40 5a inhibited the proliferation of c-KIT- and FLT3-driven AML cells in vitro and in vivo.

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

42 ls expressing R972/973 methylation-deficient FLT3 exhibited more robust apoptosis and growth inhibiti

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

44 h subsequent allele-specific upregulation of FLT3 expression, expected to lead to ligand-independent

45 ciated with contrasting variations in CD135 (FLT3) expression on cDC subsets.

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

47 T3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent.

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

49 Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene in 13q12.2 are among the most common driver e

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

51 acilitate recruitment of adaptor proteins to FLT3 in a phospho-tyrosine (Y) residue 969 (Y969) depend

52 ar to be a viable new modality for targeting FLT3 in AML and warrant further preclinical development

53 mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predomin

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

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

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

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

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

59 Our data suggest that combined menin-MLL and FLT3 inhibition represents a novel and promising therape

60 antly better responses to combined menin and FLT3 inhibition than to single-drug or vehicle control t

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

62 anism that promotes AML cell survival during FLT3 inhibition.

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

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

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

66 an oral, highly potent and selective type II FLT3 inhibitor, improves overall survival versus salvage

67 Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tande

68 tion AML cells with quizartinib, a selective FLT3 inhibitor, upregulates inflammatory genes in DTPs a

69 mutation with a highly potent and selective FLT3 inhibitor.

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

71 Mechanistically, the combination of FLT3 inhibitors and GCs enhances cell death of FLT3 muta

72 our study indicates that the combination of FLT3 inhibitors and GCs has the potential to eliminate D

73 nib, and sorafenib predict even wider use of FLT3 inhibitors going forward.

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

75 While FLT3 inhibitors like sorafenib show initial therapeutic

76 FLT3 inhibitors now emerge as an important, if not indis

77 Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 seconda

78 Despite initially responding to FLT3 inhibitors, most patients eventually relapse with d

79 unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kina

80 , even with the current FDA approval for two FLT3 inhibitors, these modalities were unable to cure AM

81 enhance current therapeutic approaches using FLT3 inhibitors.

82 Among them, compound 9u possessed nanomolar FLT3 inhibitory activities and subnanomolar inhibitory a

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

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

85 Patients with relapsed or refractory FLT3 internal tandem duplication (FLT3-ITD)-positive acu

86 ents with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) have poor outcome

87 nd drug screening, we find that treatment of FLT3 internal tandem duplication AML cells with quizarti

88 In functional studies, FLT3 internal tandem duplication gain or TP53 loss confe

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

90 of GO in female, younger (<= 70 years), and FLT3 internal tandem duplication-negative patients with

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

92 with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outco

93 ith low-level MRD before alloSCT, those with FLT3 internal tandem duplications(ITDs) had significantl

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

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

96 Although FLT3-internal tandem duplication (ITD) was an adverse ri

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

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

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

100 ith a set of additional mutations, including FLT3-internal tandem duplication and other events contri

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

102 FLT3-internal tandem duplications (FLT3-ITDs) are progno

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

104 le inhibitors of FMS-like tyrosine kinase 3 (FLT3) involved in the pathogenesis of acute myeloid leuk

105 er, our study describes a novel mechanism of FLT3 involvement in leukemogenesis by upregulation via c

106 FLT3 is a frequently mutated gene that is highly associa

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

108 While FLT3 is a viable target, the approaches to inhibit its a

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

110 ) in the fms-related tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITD(neg)) or present with a low al

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

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

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

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

115 d sensitizes progenitors to the leukemogenic FLT3(ITD) mutation.

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

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

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

119 rst composite complete remission <=6 months) FLT3-ITD acute myeloid leukaemia after standard therapy

120 improve the efficacy of kinase inhibitors in FLT3-ITD acute myeloid leukemia (AML).

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

122 ld be done in 318 of 549 trial patients with FLT3-ITD AML.

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

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

125 esults explain the less favorable outcome of FLT3-ITD APLs with ATRA-based regimens, and stress the k

126 rsenic fully rescues therapeutic response in FLT3-ITD APLs, restoring PML/RARA degradation, PML nucle

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

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

129 These findings complement our FLT3-ITD data, suggesting illegitimate TdT activity cont

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

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

132 study highlights the value of targeting the FLT3-ITD driver mutation with a highly potent and select

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

134 Net (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 muta

135 prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN

136 The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to

137 d optimized for cytotoxic activities against FLT3-ITD mutant cancer cells.

138 FLT3-ITD N-regions have a G/C content (66.9%), dinucleot

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

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

141 APL models, we unexpectedly demonstrate that FLT3-ITD severely blunts ATRA response.

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

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

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

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

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

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

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

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

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

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

152 newly diagnosed AML and centrally confirmed FLT3-ITD were eligible: 284 patients were treated, inclu

153 genetic lesions, including an association of FLT3-ITD with abundant progenitor-like cells.

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

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

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

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

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

159 5 (miR-155) is specifically overexpressed in FLT3-ITD(+) AML compared with FLT3 wild-type (FLT3-WT) A

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

161 D(neg)) or present with a low allelic ratio (FLT3-ITD(low)).

162 ted tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITD(neg)) or present with a low allelic ratio (FLT3

163 intensively treated patients with NPM1(mut)/FLT3-ITD(neg/low) AML who were prospectively enrolled in

164 Among 2,426 patients with NPM1(mut)/FLT3-ITD(neg/low) AML, 2,000 (82.4%) had a normal and 42

165 In patients with NPM1(mut)/FLT3-ITD(neg/low) AML, adverse cytogenetics were associa

166 redominates over molecular risk in NPM1(mut)/FLT3-ITD(neg/low) AML.

167 icantly associated with outcome in NPM1(mut)/FLT3-ITD(neg/low) AML.

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

169 rosine kinase 3-internal tandem duplication (FLT3-ITD) at arginines 972 and 973 by protein arginine N

170 tion in the FMS-like tyrosine kinase 3 gene (FLT3-ITD) have a poor prognosis, frequently relapse, and

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

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

173 3 mutation, the internal tandem duplication (FLT3-ITD) mutation.

174 refractory FLT3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia have a poor p

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

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

177 1q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations.

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

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

180 so showed excellent inhibitory activities in FLT3-ITD-D835V and FLT3-ITD-F691L cells which were resis

181 inhibitory activities in FLT3-ITD-D835V and FLT3-ITD-F691L cells which were resistant to quizartinib

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

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

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

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

186 ister: DRKS00000591), 83 adult patients with FLT3-ITD-positive AML in complete hematologic remission

187 the risk of relapse and death after HCT for FLT3-ITD-positive AML.

188 es of patients with a common mutation called FLT3-ITD.

189 ML patients with an MLL rearrangement and an FLT3-ITD.

190 e, SOCS2, was investigated using MLL-AF9 and Flt3-ITD/NPM1c driven mouse models of AML.

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

192 patients with AML without high allelic ratio FLT3/ITD treated in the Children's Oncology Group trial

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

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

195 with high TdT show an increased incidence of FLT3-ITDs (M0; P = .0017).

196 e "missing" microhomology in the majority of FLT3-ITDs through occult microhomology: specifically, by

197 ed the sequence and molecular anatomy of 300 FLT3-ITDs to address this issue, including 114 ITDs with

198 Understanding the origin of FLT3-ITDs would advance our understanding of the genesis

199 FLT3-internal tandem duplications (FLT3-ITDs) are prognostic driver mutations found in acut

200 pated to prime such slippage in one-third of FLT3-ITDs.

201 role for the lymphoid enzyme TdT in priming FLT3-ITDs.

202 e for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n =

203 s with fms-related tyrosine kinase 3 ligand (Flt3-L) was found to enhance translocation of intravagin

204 hen AMD3100 (day 10) was coadministered with Flt3 ligand (FL) (days 1-10) and granulocyte colony-stim

205 Flt3 ligand (Flt3L) promotes survival of lymphoid progen

206 Hence, we characterized the response to FLT3 ligand during cDC1 and cDC2 lineage differentiation

207 neage differentiation and find that although FLT3 ligand is required throughout cDC2 differentiation,

208 Overall, we find that tight regulation of FLT3 ligand levels throughout cDC differentiation dictat

209 t, combination therapy with CD40 agonist and Flt3 ligand restores cDC1 abundance to normal levels, de

210 ted the antitumor effect of PD-1 antibody or Flt3 ligand, and induced the presentation of a TAP-indep

211 e CD4 T cells, trapping the cells in a naive Flt3 ligand-expressing state.

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

213 topologically associated domain (TAD) at the FLT3 locus, which results in higher expression of FLT3,

214 its oncogenic function in MLL-r ALL cells is FLT3 methylation dependent.

215 lls expressed CSF1R alongside high levels of FLT3, MHCII, XCR1, and other markers associated with con

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

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

218 T3 inhibitors and GCs enhances cell death of FLT3 mutant, but not wild-type, cells through GC-recepto

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

220 , mutational drug resistance, and relapse in FLT3-mutant AML.

221 le TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-r

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

223 The natural history of FLT3-mutated AML is changing after the approval of midos

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

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

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

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

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

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

230 ith NPM1mut or MLL-r leukemia and concurrent FLT3 mutation.

231 ine NPM1mut and MLL-r leukemias harboring an FLT3 mutation.

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

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

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

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

236 FLT3 mutations are prevalent in AML patients and confer

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

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

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

240 on AML cells harboring resistance-conferring FLT3 mutations.

241 We have examined the CD34+c-Kit+Flt3+ myeloid progenitor population as potential mutatio

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

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

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

245 ons in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common

246 tically, UC-MSCs express FLT3L that binds to FLT3 on CD1c(+)DCs to promote the proliferation and inhi

247 ied one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this associat

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

249 eficial in patients who lacked a mutation of FLT3 or NPM1, had < 3 mutations in other genes, or had a

250 le cytogenetics, those lacking a mutation of FLT3 or NPM1, or those with < 3 other mutations may deri

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

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

253 clones activating signaling pathways such as FLT3 or RAS or biallelically perturbing TP53.

254 ociated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival.

255 To develop a new modality for targeting FLT3, our team engineered an alpha-FLT3-A192 fusion prot

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

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

258 specific small-molecule kinase inhibitors of FLT3 phosphorylation resulted in a significantly superio

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

260 high- and low-risk LCH patients, CD34+c-Kit+Flt3+ progenitor frequency in blood was higher than in h

261 CD34+c-Kit+Flt3+ progenitors from blood of both high- and low-risk

262 ts in increased cis interactions between the FLT3 promoter and another enhancer located distally to t

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

264 t leukemia cell viability parallels baseline FLT3 R972/973 methylation levels.

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

266 FLT3 receptor is an important therapeutic target in acut

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

268 Targeted therapies against the FLT3 receptor, including small-molecule FLT3 tyrosine ki

269 9u exhibited over 40-fold selectivity toward FLT3 relative to c-Kit kinase, which might reduce myelos

270 48c, induced necrosis in several mutant and FLT3-resistant AML cell lines and primary blasts from AM

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

272 FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gate

273 ia (APL) is often associated with activating FLT3 signaling mutations.

274 riptional suppression of genes downstream of FLT3 signaling.

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

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

277 fit of midostaurin was consistent across all FLT3 subtypes.

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

279 firmed long-range co-regulation of SOCS2 and FLT3 through changes in promoter conformation.

280 cate a new mechanism, how NPM1c mislocalizes FLT3-TKD and changes its signal transduction ability.

281 but also in patients with AML with combined FLT3-TKD and NPM1c mutations.

282 r, NPM1c alters the cellular localization of FLT3-TKD from the cell surface to the endoplasmic reticu

283 Mechanistically, we could show that FLT3-TKD is able to activate the downstream effector mol

284 Although expression of FLT3-TKD is not sufficient to induce a disease in mice,

285 d the effect of the coincidence of NPM1c and FLT3-TKD.

286 -labelling cells expressing Cx3cr1, Csf1r or Flt3-to identify the precursors of osteoclasts in mice.

287 tion than did Y969 phosphorylation-deficient FLT3-transduced cells.

288 ance to patients with point mutations of the FLT3 tyrosine kinase domain (TKD), but the biological me

289 Finally, combining FLT3 tyrosine kinase inhibitor PKC412 with MS023 treatme

290 the FLT3 receptor, including small-molecule FLT3 tyrosine kinase inhibitors (TKIs) and anti-FLT3 ant

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 reas AML cells with wild-type NPM1, MLL, and FLT3 were not affected by either of the 2 drugs.

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

297 and shorter overall survival than those with FLT3 wild-type disease.

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

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(