ライフサイエンスコーパス: MTAP

1 MTAP deletion and mutational activation of KRAS create t

2 MTAP deletion occurs in 10-15% of all human cancers due

3 MTAP differs from previous attempts at regulatory motif

4 MTAP encodes the enzyme methylthioadenosine phosphorylas

5 MTAP expression causes a significant decrease in intrace

6 MTAP expression does not affect the growth rate of cells

7 MTAP is a ubiquitously expressed homotrimeric-subunit en

8 MTAP is abundant in normal cells but is deficient in man

9 MTAP is frequently lost due to its proximity to the comm

10 MTAP loss causes accumulation of methylthioadenosine (MT

11 MTAP presents a new approach to the challenging problem

12 MTAP(+) normal keratinocytes and pancreatic carcinoma li

13 MTAP(-) T-ALL-derived cell line, CEM cells were very sen

14 MTAP-deleted cells accumulate the metabolite methylthioa

15 MTAP-negative A549 lung cancer cells were transfected wi

16 respond to pemetrexed as compared to 1 of 10 MTAP-proficient patients.

17 te methylthioribosyltransferase, EC 24.2.28; MTAP) plays a role in purine and polyamine metabolism an

18 Furthermore, a historic cohort shows 4 of 4 MTAP(def) patients respond to pemetrexed as compared to

19 al studies have shown ICI resistance in 9p21/MTAP null/low patients, we propose that MTA degrading th

20 or in combination with a salvage agent as a MTAP-selective therapy and therefore lay the foundation

21 Mice homozygous for a MTAP null allele (Mtap(lacZ)) have an embryonic lethal p

22 L-alanosine can be increased by the use of a MTAP substrate, which protects MTAP+ normal cells.

23 A is effective for in vivo treatment of A549 MTAP(-/-) and H358 MTAP(+/+) tumors.

24 In addition, MTAP-expressing cells are suppressed for tumor formation

25 In addition, MTAP-knockdown increases sensitivity to pemetrexed.

26 linical trials for the treatment of advanced MTAP-deleted solid tumors.

27 action certain antifolates may have against MTAP-deficient malignancies.

28 and dysregulated alternative splicing of all MTAP isoforms.

29 al role in tumorigenesis, we have created an MTAP-knockout mouse.

30 was able to induce antitumor response in an MTAP knockout HCT116 xenograft model.

31 Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 dependence.

32 r in MCF7, a breast cancer cell line with an MTAP gene deletion.

33 wth of both MTAP(+) (Molt-4 and Molt-16) and MTAP(-) (CEM and HSB2) cell lines.

34 ons of 9p21 that inactivate CDKN2A, ARF, and MTAP are common in a wide variety of human cancers.

35 Deletions of CDKN2A/B and MTAP genes were more frequent in cell lines than tumor s

36 tion-state analogues designed for HpMTAN and MTAP show significant overlap in specificity.

37 Furthermore, normal lymphocytes and MTAP+ primary T-ALL cells were rescued from L-alanosine

38 st gene flanking each side being MIR31HG and MTAP, neither of which has been implicated in BMD or BMC

39 tend to have reduced levels of Mtap mRNA and MTAP protein in addition to unaltered levels of methylde

40 16 tumor suppressor gene (2 of 7 tumors) and MTAP gene (3 of 7).

41 which can physically interact with archetype MTAP, have been identified.

42 Approximately 15% of human cancers are MTAP(-/-).

43 inhibitor of de novo AMP synthesis, than are MTAP+ primary T-ALL cells.

44 tal adenocarcinoma (PDAC), ~22% of which are MTAP-del, and demonstrated that BMS-986504 suppressed PR

45 tion of point mutations with cancer, such as MTAP and MAGED1.

46 Because MTAP phosphorolyzes 5'-deoxy-5'-methylthioadenosine (MTA

47 samples showed a frequent breakpoint between MTAP exon 4 and exon 5.

48 xobutanoic acid represses ODC levels in both MTAP-deleted yeast and human tumor cell lines, indicatin

49 AMP synthesis, inhibited the growth of both MTAP(+) (Molt-4 and Molt-16) and MTAP(-) (CEM and HSB2)

50 by the MTAP substrate 5'-deoxyadenosine, but MTAP-T-ALL cells were not.

51 of 5'-methylthioadenosine (MTA) catalyzed by MTAP and were corrected for the forward commitment to ca

52 hioadenosine (MTA, the metabolite cleaved by MTAP) in cells harboring MTAP deletions.

53 MTA is found because of catabolism of MTA by MTAP.

54 ed in polyamine synthesis and is recycled by MTAP to S-adenosyl-L-methionine (SAM) via salvage pathwa

55 omic profiling, we show that MTA secreted by MTAP-deleted cells in vitro results in high levels of ex

56 the 4-5% of cancer patients harboring CDKN2A/MTAP deletion and MAPK alterations.

57 ergized with PRMT5 inhibition to kill CDKN2A/MTAP-null, RAS-active tumors.

58 ad tumors with homozygous deletion of CDKN2A/MTAP and/or loss of MTAP protein by immunohistochemistry

59 Six distinct retroviral-sequence-containing MTAP isoforms, each of which can physically interact wit

60 In contrast, MTAP(-) cell lines, which cannot recycle purines from en

61 t of six samples with intact p16 but deleted MTAP locus.

62 o 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells.

63 ee of the four cell lines lacking detectable MTAP protein were unable to grow in Hcy-containing media

64 r hypermethylation was shown to downregulate MTAP expression and may represent a mechanism of MTAP in

65 sible alterations of p53, PTEN, K-ras, EGFR, MTAP, and p16 (MTS1/CDKN2) genes.

66 ccharomyces cerevisiae the MEU1 gene encodes MTAP and that Meu1delta cells have an 8-fold increase in

67 The gene encoding MTAP, MTAP, is frequently codeleted along with the tumor

68 with eukaryotic expression vectors encoding MTAP cDNA in sense and antisense orientations.

69 fficacious in mouse xenografts of endogenous MTAP-null tumors such as BxPC-3 (96% TGI @ 100 mg/kg QD)

70 that, in addition to deletion of the entire MTAP gene, a common break point was between exons 4 and

71 These data provide rationale to explore MTAP status as a biomarker strategy for patient selectio

72 hionine depletion than were cells expressing MTAP protein (sense transfectoma).

73 se, and this flux increases 2-fold following MTAP deletion.

74 9p is uncertain, and the molecular basis for MTAP deficiency in cancer is unknown.

75 s that have an identical genotype except for MTAP status.

76 e may be selection in early stages of MF for MTAP deletion within the cutaneous tumor microenvironmen

77 nhibitors are the most powerful reported for MTAP and have sufficient affinity to be useful in inhibi

78 the tightest binding inhibitor reported for MTAP.

79 proved DMPK properties that is selective for MTAP-deleted cancers and is currently in Phase I/II clin

80 sine (2AMTA) as an alternative substrate for MTAP and MTAN enzymes.

81 Methylthioadenosine (MTA), the substrate for MTAP, is formed in polyamine synthesis and is recycled b

82 rationale for their combination therapy for MTAP-deleted, KRAS-mutant pancreatic cancer.

83 her investigation as a potential therapy for MTAP/CDKN2A-deleted tumors.

84 enosine, is a highly selective treatment for MTAP-negative cancers.

85 referential impairment of cell viability for MTAP-null cancer cell lines compared with isogenic MTAP-

86 Furthermore, MTAP knockdown in normal erythroblasts was shown to enha

87 Furthermore, MTAP-deleted cells, which harbor an attenuated PRMT5-MEP

88 SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two ext

89 ified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, and ZNF668) in which NM/SSM-specifi

90 ed overexpression of metabolism-related gene MTAP (methylthioadenosine phosphorylase) in SSM resulted

91 the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methyl

92 ors are now in clinical trials for genotypic MTAP(-/-) cancers, however the MTAP(-/-) genotype repres

93 in vivo treatment of A549 MTAP(-/-) and H358 MTAP(+/+) tumors.

94 tabolite cleaved by MTAP) in cells harboring MTAP deletions.

95 e that inhibited the proliferation of HCT116 MTAP-deleted cells with ~40x selectivity over HCT116 MTA

96 eted cells with ~40x selectivity over HCT116 MTAP-WT cells.

97 Homozygous MTAP deletion occurs in ~15% of cancers, making them vul

98 Homozygous MTAP-deleted cell lines in culture show elevation of MTA

99 ese data show a high frequency of homozygous MTAP deletions in NSCLC which is associated with detecta

100 KN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sens

101 Human MTAP is characterized by a late S(N)1 transition state w

102 n the picomolar range while inhibiting human MTAP with orders of magnitude weaker affinity.

103 s for the proposed transition state of human MTAP on the basis of the known ribooxacarbenium characte

104 The more enclosed catalytic sites of human MTAP require the inhibitors to adopt a folded structure,

105 The X-ray crystal structure of human MTAP with bound MT-Imm-A also reveals that the 5'-methyl

106 Interaction of 2AMTA with human MTAP was also characterized by pre-steady-state kinetics

107 We kinetically characterize 2AMTA with human MTAP, bacterial MTANs and use 2,6-diaminopurine as a flu

108 Thus, MTA accumulation in MTAP-deleted cancers creates a hypomorphic PRMT5 state t

109 x and selectively inhibits PRMT5 activity in MTAP-deleted cells compared to MTAP-wild-type cells.

110 Of 23 malignant cell lines deficient in MTAP protein, all but one had complete or partial deleti

111 ne putrescine stimulates colony formation in MTAP-expressing cells.

112 suppressed PRMT5 function and cell growth in MTAP-del cells and xenograft models.

113 RMT5, known synthetic-lethal interactions in MTAP(-/-) cancer cell lines.

114 nation therapy mimics synthetic lethality in MTAP(+/+) CRC cell lines with similar effects in mouse x

115 , selectively induces synthetic lethality in MTAP-deleted tumor cells.

116 ric dimethylarginine protein modification in MTAP-deleted tumors that correlated with antitumor activ

117 Expression of MTAP in MTAP-deleted MCF-7 breast adenocarcinoma cells results i

118 Deletion of MTAP in MTAP-proficient cells rendered them sensitive to PRMT5 d

119 al (NCT02693717) that assesses pemetrexed in MTAP(def) urothelial carcinoma (UC) with the primary end

120 itor, AM-9934, selectively inhibits PRMT5 in MTAP-deleted cells and in transplanted tumors while spar

121 -state levels of sDMA-containing proteins in MTAP+ cells, even though no sustained increase in intrac

122 e identified strongly associated variants in MTAP, a gene adjacent to the familial melanoma susceptib

123 g to a potent reduction of cell viability in MTAP-del cells compared to MTAP-WT cells.

124 ding to specific suppression of viability in MTAP-deleted cells.

125 d cells with MT-DADMe-ImmA and MTA inhibited MTAP, increased cellular MTA concentrations, decreased p

126 However, when we introduced MTAP cDNA into MTAP-deficient MCF-7 cells, the resulting cell line was

127 e that normal cells, which are intrinsically MTAP+, would be protected from L.-alanosine toxicity, wh

128 However, when we introduced MTAP cDNA into MTAP-deficient MCF-7 cells, the resulting

129 ull cancer cell lines compared with isogenic MTAP-expressing counterparts.

130 on profiles in GBM samples revealed that low MTAP expression is correlated with an increased proporti

131 th SAM, MTA partially inhibits PRMT5, making MTAP-deleted tumors susceptible to further PRMT5 inhibit

132 In this work, we propose a method (MTAP) that substantially reduces the effort required to

133 Importantly, in early stage MF, MTAP loss occurred independently of CDKN2A loss in 37% o

134 The gene encoding MTAP, MTAP, is frequently codeleted along with the tumor suppr

135 ed (MTAP-null) cells compared to MTAPintact (MTAP WT) cells.

136 lished BATTLE2 clinical trial (NCT01248247), MTAP(def) associates with an improved response rate to p

137 struct (antisense transfectoma) expressed no MTAP protein and were more sensitive to both purine and

138 hesized and evaluated a potentially nontoxic MTAP substrate, 9-beta-D-erythrofuranosyladenine (EFA).

139 have only been tested in naturally occurring MTAP-positive and -negative cell lines, which might have

140 e other hand, the IC50 for 60% (12 of 20) of MTAP+ primary T-ALL was 19+/-18 microM (range, 1.7-67 mi

141 se chain reaction amplification of exon 8 of MTAP showed a deletion in 16 of 48 (33.3%) patients at d

142 luoromethylornithine inhibits the ability of MTAP-deficient cells to form colonies in soft agar, wher

143 s to be because of the enzymatic activity of MTAP, as a protein with a missense mutation in the activ

144 e inhibitors can leverage the consequence of MTAP deletion, namely, accumulation of the MTAP substrat

145 The finding of frequent deficiency of MTAP in T-ALL offers the possibility of an enzyme target

146 Co-deletion of MTAP and methionine adenosyltransferase 2 alpha (MAT2a)

147 ability for tumors carrying a co-deletion of MTAP and the adjacent CDKN2A tumor suppressor gene.

148 Deletion of MTAP in MTAP-proficient cells rendered them sensitive to

149 Homozygous deletions of MTAP exon 8 could be detected in 19 of 50 NSCLC samples

150 MAT2A is downstream of MTAP action and catalyzes synthesis of the SAM necessary

151 putative salvage pathway genes downstream of MTAP also cause elevated ODC activity and elevated polya

152 eted cell lines in culture show elevation of MTAP's substrate metabolite, methylthioadenosine (MTA).

153 y marks the first report of the existence of MTAP in any bacterium.

154 Expression of MTAP in MTAP-deleted MCF-7 breast adenocarcinoma cells r

155 The sole function of MTAP is to recycle 5'-methylthioadenosine (MTA) to S-ade

156 The function of MTAP is to salvage methylthioadenosine, which is produce

157 ubstrate adaptor interface impairs growth of MTAP-null tumor cells and is thus a site for development

158 MTDIA causes a physiologic inactivation of MTAP and may also have efficacy in combination with inhi

159 Inactivation of MTAP, often by homozygous deletion, is found in both sol

160 Here, we show that inhibition of MTAP alongside SSAT upregulation is synergistic in andro

161 adenosine (MTA) was blocked by inhibition of MTAP with methylthio-DADMe-Immucillin-A (MTDIA), an oral

162 hree-transition-state analogue inhibitors of MTAP and MTAN.

163 lex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (M

164 DKN2A occurred in 18% of samples but loss of MTAP alone was uncommon.

165 Loss of MTAP leads to significantly increased cellular levels of

166 To determine if loss of MTAP plays a functional role in tumorigenesis, we have c

167 ygous deletion of CDKN2A/MTAP and/or loss of MTAP protein by immunohistochemistry.

168 expression and may represent a mechanism of MTAP inactivation.

169 e clone containing a processed pseudogene of MTAP.

170 Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 depend

171 The specific role of MTAP in cutaneous T-cell lymphoma subgroups, mycosis fun

172 Deep sequencing of MTAP/CDKN2A-CDKN2B loci in 77 peripheral blood mononucle

173 stitute an effective therapy for a subset of MTAP-positive tumors.

174 ion of methylthioadenosine, the substrate of MTAP, protected the MTAP(+) cells but not the MTAP(-) ce

175 aging antitumor activity across a variety of MTAP-deleted solid tumors was observed based on objectiv

176 line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of

177 T5 by MTA accumulation is a vulnerability of MTAP-deleted cancers.

178 ility of MAT2a inhibitors in these and other MTAP(+/+) cancers.

179 trials for the treatment of T-ALL and other MTAP-deficient malignancies with L-alanosine.

180 ase adenine, loss of this pathway in p16(-), MTAP(-) cells might sensitize these cells to methotrexat

181 pancreatic carcinoma cell lines were p16(-), MTAP was codeleted in all five cases.

182 ifolates such as methotrexate than are p16+, MTAP+ cells.

183 e gene order on chromosome 9p2l is p15, p16, MTAP, IFNA, and interferon beta gene (IFNB).

184 p16-, MTAP- malignant cells have been shown to be more suscept

185 we reintroduced MTAP activity into two p16-, MTAP- cell model systems, the MiaPaCa-2 and PANC-1 human

186 ral PRMT5 inhibition was confirmed in paired MTAP-deleted tumor biopsies, and molecular responses (ci

187 5'-Methylthioadenosine phosphorylase (MTAP) and 5'-methylthioadenosine nucleosidase (MTAN) cat

188 -deoxy-5'-methylthioadenosine phosphorylase (MTAP) and the genes of the IFN-alpha and -beta cluster (

189 Methylthioadenosine phosphorylase (MTAP) and the tumor suppressor genes CDKN2A-CDKN2B are f

190 ied as 5'-methylthioadenosine phosphorylase (MTAP) based on its biochemical properties and mass spect

191 (CDKN2A)/methylthioadenosine phosphorylase (MTAP) codeletion occurs frequently in non-small cell lun

192 he enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine

193 zygous 5'-methylthioadenosine phosphorylase (MTAP) deletions occur in approximately 15% of human canc

194 Loss of Methylthioadenosine Phosphorylase (MTAP) expression, via gene deletion or epigenetic silenc

195 The human methylthioadenosine phosphorylase (MTAP) gene is located on 9p21 and is frequently homozygo

196 on of the methylthioadenosine phosphorylase (MTAP) gene results in accumulation of methylthioadenosin

197 enzyme 5'-methylthioadenosine phosphorylase (MTAP) has been implicated as both a cancer target and a

198 letion of methylthioadenosine phosphorylase (MTAP) in cancers such as glioblastoma represents a poten

199 ciency of methylthioadenosine phosphorylase (MTAP) in T-cell acute lymphoblastic leukemia (T-ALL) and

200 letion of methylthioadenosine phosphorylase (MTAP) is a common genomic alteration in human tumors but

201 5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway.

202 Human methylthioadenosine phosphorylase (MTAP) is a purine and methionine metabolic enzyme presen

203 Methylthioadenosine phosphorylase (MTAP) is an important enzyme for the salvage of adenine

204 -Deoxy-5'-methylthioadenosine phosphorylase (MTAP) is involved in the salvage of adenine and methylth

205 N2A/B and methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic deletions in c

206 letion of methylthioadenosine phosphorylase (MTAP) occurs in ~10%-15% of solid tumors.

207 s lacking methylthioadenosine phosphorylase (MTAP), a common genetic event associated with poor progn

208 ession of methylthioadenosine phosphorylase (MTAP), a key enzyme in the salvage pathway.

209 Human 5'-methylthioadenosine phosphorylase (MTAP), a reported anticancer target, catalyzes phosphoro

210 Methylthioadenosine phosphorylase (MTAP), an enzyme essential for the salvage of adenine an

211 Methylthioadenosine phosphorylase (MTAP), an enzyme involved in purine and methionine metab

212 ciency of methylthioadenosine phosphorylase (MTAP), both located on chromosome 9p21, have been indepe

213 ay enzyme methylthioadenosine phosphorylase (MTAP), frequently deleted in cancer, affects methionine

214 encoding methylthioadenosine phosphorylase (MTAP), the initial enzyme in the methionine salvage path

215 relies on methylthioadenosine phosphorylase (MTAP), the rate-limiting enzyme, to relieve strain.

216 ping gene methylthioadenosine phosphorylase (MTAP).

217 ion of 5'-methylthioadenosine phosphorylase (MTAP).

218 ion of 5'-methylthioadenosine phosphorylase (MTAP).

219 human 5'-methylthioadenosine phosphorylase (MTAP).

220 human 5'-methylthioadenosine phosphorylase (MTAP).

221 Methythioadenosine phosphorylase (MTAP) functions solely in the polyamine pathway of mamma

222 yme methylthioadenosine (MTA) phosphorylase (MTAP) in 36% of lines, transcription factor DMRTA1 (27%)

223 encoding methylthioadenosine phosphorylase, MTAP.

224 ancer genes, including deletions in PPP2R2A, MTAP and MAP2K4.

225 EFA at 20 microM or less rescued primary MTAP+ T-ALL cells and normal lymphocytes from L-alanosin

226 the use of a MTAP substrate, which protects MTAP+ normal cells.

227 MTAP copy number loss (P < 0.01) but reduced MTAP expression was also detected in the absence of copy

228 In CD4(+) cells from SS, reduced MTAP mRNA expression correlated with MTAP copy number lo

229 We have reintroduced MTAP into MCF-7 breast adenocarcinoma cells and have exa

230 nd the underlying mechanism, we reintroduced MTAP activity into two p16-, MTAP- cell model systems, t

231 The remainder can be rendered MTAP(-) through MTAP inhibitors.

232 AP-dependent adenine salvage pathway renders MTAP+ cells less dependent on de novo purine synthesis a

233 In addition, EFA selectively rescued MTAP+ MOLT-4 cells from L-alanosine toxicity at 25 micro

234 that EFA is an effective agent for salvaging MTAP+ cells from L-alanosine toxicity and is superior to

235 ethyltransferase 5 (PRMT5), which sensitizes MTAP-deleted cells to PRMT5 and methionine adenosyltrans

236 ne incorporation, DNA synthesis in all seven MTAP-primary T-ALL cells was inhibited by L-alanosine wi

237 Since MTAP substrates MTA and 5'deoxyadenosine are prone to to

238 0 loci (TYR, AFG3L1P, CDK10, MYH7B, SLC45A2, MTAP, ATM, CLPTM1L, FTO, and CASP8) that have previously

239 lls and in transplanted tumors while sparing MTAP-expressing counterparts, leading to specific suppre

240 n 213 skin samples from patients with MF/SS, MTAP copy number loss (34%) was more frequent than CDKN2

241 IA antitumor activity in xenografts supports MTAP as a target for lung cancer therapy.

242 thereby allowing them to selectively target MTAP-deleted cancer cells.

243 e PRMT5 inhibitor EZP015556, shown to target MTAP (a gene commonly lost in pancreatic cancer)-negativ

244 indings suggest the possibility of targeting MTAP for selective therapy of T-ALL.

245 ne synthesis and hence less susceptible than MTAP- malignant cells to the growth-inhibitory actions o

246 Here, we confirm that MTAP-deleted cells have increased MTA accumulation and r

247 We demonstrate that MTAP- T-ALL cells obtained at relapse are as sensitive t

248 These results indicate that MTAP deficiency in cancer is primarily due to codeletion

249 These results indicate that MTAP has tumor suppressor activity and suggest that its

250 These results prove that MTAP deficiency contributes directly to the sensitivity

251 We now report that MTAP-primary T-ALL cells are more sensitive to the toxic

252 Here we show that MTAP loss in GBM cells is correlated with differential e

253 Here we show, that MTAP deletion is negatively prognostic in MPM.

254 late polyamine biosynthesis and suggest that MTAP deletion may lead to ODC activation in human tumors

255 sic KIEs (1'-(14)C and 9-(15)N) suggest that MTAP has a dissociative S(N)1 transition state with its

256 The MTAP gene consists of eight exons and seven introns.

257 The MTAP gene is frequently deleted in human cancers because

258 Because the MTAP gene is located adjacent to the tumor-suppressor ge

259 from endogenously generated MTA, because the MTAP inhibitor 5'-chloro-5'-de- oxyformycin A potentiate

260 fection with MTAP cDNA (i) restored both the MTAP-dependent adenine and methionine salvage pathways,

261 ere rescued from L-alanosine toxicity by the MTAP substrate 5'-deoxyadenosine, but MTAP-T-ALL cells w

262 We have cloned the MTAP gene, and have constructed a topologic map of the 9

263 for genotypic MTAP(-/-) cancers, however the MTAP(-/-) genotype represents fewer than 2% of human col

264 cally interacts with the CDKN2A/B locus, the MTAP gene and an interval downstream of IFNA21.

265 TAP, protected the MTAP(+) cells but not the MTAP(-) cells from alanosine toxicity.

266 cancer is primarily due to codeletion of the MTAP and p16 genes.

267 cancer cells with homozygous deletion of the MTAP gene if the inhibitors can leverage the consequence

268 the p16 gene, we examined the status of the MTAP gene in T-ALL patients.

269 Deletion of the MTAP gene leads to accumulation of the substrate of the

270 Partial or total deletions of the MTAP gene were found in primary T-cell acute lymphoblast

271 eads to accumulation of the substrate of the MTAP protein, methylthioadenosine (MTA).

272 f MTAP deletion, namely, accumulation of the MTAP substrate MTA.

273 However, the order of the MTAP, p16, p15, and IFNA genes on chromosome 9p is uncer

274 support the hypothesis that operation of the MTAP-dependent adenine salvage pathway renders MTAP+ cel

275 Hcy-containing media, whereas all six of the MTAP-positive cell lines tested showed strong growth.

276 nosine, the substrate of MTAP, protected the MTAP(+) cells but not the MTAP(-) cells from alanosine t

277 Previously, we reported that the MTAP gene was deleted in over 30% of T-ALL patients at b

278 Thus the MTAP loss in malignant cells may be an example of gene d

279 The sequence is 92% homologous to the MTAP cDNA, is flanked at its 3' end by a repetitive elem

280 This may be in part due to the MTAP-dependent salvage of adenine moieties from endogeno

281 Intriguingly, two of these MTAP exons arose from early and independent retroviral-i

282 e antipurine actions of MTX in some of these MTAP(+) lines.

283 he remainder can be rendered MTAP(-) through MTAP inhibitors.

284 10(-14) for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A (P = 4.03 x 10(-7) for rs702332

285 5 activity in MTAP-deleted cells compared to MTAP-wild-type cells.

286 cell viability in MTAP-del cells compared to MTAP-WT cells.

287 hionine uptake, with no major changes due to MTAP deletion.

288 fic for p16INK4A exon 3, the exon nearest to MTAP exon 8.

289 are differentially sDMAylated in response to MTAP and MTA.

290 cells may be exploited to selectively treat MTAP-negative cancers by inhibiting de novo purine synth

291 arm of human chromosome 9 at band p21, where MTAP and interferon alpha genes (IFNA) also map.

292 rotected from L.-alanosine toxicity, whereas MTAP-tumor cells would be killed.

293 morigenesis is well established, but whether MTAP loss directly affects tumorigenesis is unclear.

294 ad to selective killing of cancer cells with MTAP deletion.

295 is suggested focal deletions consistent with MTAP and CDKN2A copy number loss detected with quantitat

296 reduced MTAP mRNA expression correlated with MTAP copy number loss (P < 0.01) but reduced MTAP expres

297 loration evaluating AMG 193 in patients with MTAP-deleted solid tumors.

298 We further investigated the ten samples with MTAP deletions but intact p16INK4A exon 1alpha with prim

299 at formed an in frame fusion transcript with MTAP in a glioma xenograft, and that is homozygously del

300 It was found that transfection with MTAP cDNA (i) restored both the MTAP-dependent adenine a

301 c carcinoma cell lines, by transfection with MTAP cDNA.