ライフサイエンスコーパス: SMARCB1

1 ag1, Lgals3, Lypd3, Nme1, Ptges2, Ptgs1, and Smarcb1).

2 a class of drugs effective against PTCL-NOS(Smarcb1-).

3 haracterized by loss of the tumor suppressor SMARCB1.

4 elioid sarcoma characterised by loss of INI1/SMARCB1.

5 rringtonine were dependent on the absence of SMARCB1.

6 ssembled SWI/SNF complexes in the absence of SMARCB1.

7 tial for SWI/SNF integrity in the absence of SMARCB1.

8 underlying the tumor-suppressive activity of SMARCB1.

9 n of wild-type SS18 and the tumor suppressor SMARCB1.

10 ed schwannomatosis cases lacking mutation in SMARCB1.

11 Snf5 (Ini1/Baf47/Smarcb1), a core member of the Swi/Snf chromatin remodel

12 tly associated with inactivation of the gene SMARCB1, a conserved subunit of the chromatin remodeling

13 The highest priority gene was SMARCB1, a core member of the SWI/SNF complex which prom

14 We show that loss of SMARCB1, a subunit of the SWI/SNF (BAF) complex mutated

15 childhood characterized by biallelic loss of SMARCB1, a subunit of the SWI/SNF chromatin remodeling c

16 ten characterized by deletion or mutation of SMARCB1, a tumor suppressor gene.

17 bation of cell fate, shows that depletion of Smarcb1 activates the Myc network, driving an anabolic s

18 Here, we report how loss of SMARCB1 affects the epigenome in these tumors.

19 schwannoma but no mutation of the remaining SMARCB1 allele in blood and tumor samples.

20 ss-of-function intronic fusion events in one SMARCB1 allele with concurrent loss of the other allele.

21 , and fluorescence in situ hybridization for SMARCB1 (also known as hSNF5/INI1) deletion.

22 SMARCB1 (also known as SNF5, INI1, and BAF47), a core su

23 in demographics, tumor location, and type of SMARCB1 alterations, were identified.

24 rant HML-2 activation, which is dependent on SMARCB1 and its interaction with MYC.

25 -type renal tumors exhibited lower levels of SMARCB1 and more aggressive growth in mice harboring the

26 omatic loss of one copy of 22q, encompassing SMARCB1 and NF2, with a different somatic mutation of th

27 Two genes, SMARCB1 and PARP1, whose modulation by SAHA and RMD is p

28 CM) protein and chromatin-remodeling complex SMARCB1 and SMARCC2 to be LXA4-interacting host proteins

29 gressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait.

30 -specific conditional knockout mice carrying Smarcb1 and/or Nf2 deletion.

31 luding CDKN1B, SAMHD1, BCOR, SYNE1, HNRNPH1, SMARCB1, and DAZAP1.

32 ients with schwannoma were screened for NF2, SMARCB1, and LZTR1 gene mutations, while patients with m

33 ce neurography and mutation analysis of NF2, SMARCB1, and LZTR1.

34 CML cells to imatinib treatment: PTPN1, NF1, SMARCB1, and SMARCE1, and 5 regulators of the response t

35 x-gene model, including PARP1, EP300, KDM5C, SMARCB1, and UHRF1 matched this pattern.

36 The SWI/SNF core subunits SMARCE1 and SMARCB1 are displaced from enhancers but are bound to pr

37 pose that residual SWI/SNF complexes lacking SMARCB1 are vital determinants of drug sensitivity, not

38 malian SWItch/sucrose nonfermentable subunit SMARCB1, are very aggressive childhood cancers that can

39 extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene.

40 The isolation of SMARCB1-associated transcripts, together with chromatin

41 understand the origin of these two types of SMARCB1-associated tumors, we generated different tissue

42 e coiled-coil C-terminal domain (CTD) of the SMARCB1 (BAF47) subunit, which cause the intellectual di

43 inactivation of the core BAF complex subunit SMARCB1 (BAF47).

44 own as SMARCD or BAF60), Snf5 (also known as SMARCB1, BAF47 or INI1) and an asymmetric dimer of Swi3

45 SNF5 (INI1/SMARCB1/BAF47) is a tumor suppressor that regulates the

46 extremely low rate of mutation, with loss of SMARCB1 being essentially the sole recurrent event.

47 r network of pro-oncogenic genes by favoring SMARCB1 binding.

48 We found that SMARCB1 binds adjacent to the HML-2 promoter, repressing

49 INI1/SMARCB1 binds to HIV-1 integrase (IN) through its Rpt1 d

50 After 72 hours of induction of SMARCB1, both SMARCB1-negative PD chordoma cell lines co

51 t of a sarcoma mutant in the SWI/SNF subunit SMARCB1, but resistance occurs.

52 Furthermore, we analyzed SMARCB1 by fluorescence in situ hybridization and multip

53 ome H2A/H2B acidic patch regions through the SMARCB1 C-terminal alpha-helix and the SMARCA4/2 C-termi

54 Inactivating mutations in SMARCB1 confer an oncogenic dependency on EZH2 in atypic

55 in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting o

56 While SMARCB1-containing SWI/SNF complexes are bound preferent

57 tivation by profiling the RNA interactome of SMARCB1-containing SWI/SNF complexes in proliferating an

58 that SMARCB1 deficiency, defined as genomic SMARCB1 copy number loss associated with reduced mRNA, d

59 We find that the SMARCB1 CTD contains a basic alpha helix that binds dire

60 utionarily conserved structural role for the SMARCB1 CTD that is perturbed in human disease.

61 nerated from SMARCB1 KO tumors that predicts SMARCB1 deficiency in patients.

62 Here, we demonstrate that SMARCB1 deficiency, defined as genomic SMARCB1 copy numb

63 ion of STAT3 inhibitors for the treatment of SMARCB1-deficient bladder cancer.

64 tify a synthetic lethal relationship between SMARCB1-deficient cancers and reliance on the UPS which

65 monstrate that dependency on Phf6 extends to Smarcb1-deficient cancers in vivo.

66 rse, one class composed of highly aggressive SMARCB1-deficient carcinomas and another class with tumo

67 We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activati

68 of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.

69 rthotopic cell line-derived xenografts and a SMARCB1-deficient patient derived xenograft model.

70 After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind t

71 nes and primary tumors exhibit similarity to SMARCB1-deficient tumor types.

72 SMARCB1-deficient tumors show an increased IL6/JAK/STAT3

73 scues the viral mimicry response to EZH2i in SMARCB1-deficient tumors.

74 le pathways driving growth and metastasis in SMARCB1-deficient tumors.

75 environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells,

76 results demonstrate a physiological role for SMARCB1 degradation in response to hypoxic stress, conne

77 Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic s

78 poptosis and differentiation specifically in SMARCB1-deleted MRT cells.

79 revalent association to active regions where SMARCB1 differentially binds locally transcribed RNAs.

80 SMARCB1 encodes the SNF5 subunit of the SWI/SNF chromati

81 Biallelic inactivation of SMARCB1, encoding a member of the SWI/SNF chromatin remo

82 e identify SWINGN, a lncRNA interacting with SMARCB1 exclusively in proliferating conditions, exertin

83 Exon scanning of all nine SMARCB1 exons in genomic DNA from our cohort of families

84 hromatin immunoprecipitation; restoration of SMARCB1 expression in AT/RT cell lines significantly dow

85 V-K LTR significantly more in the absence of SMARCB1 expression in AT/RT cells.

86 in human ALL cell lines confirmed that lower SMARCB1 expression increased prednisolone resistance.

87 ive PD chordoma cell lines with an inducible SMARCB1 expression system were generated.

88 ating from notochordal tissue, shows loss of SMARCB1 expression, a core component of the Switch/Sucro

89 odels revealed that RMC requires the loss of SMARCB1 for survival.

90 quently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated

91 on of biallelic, truncating mutations of the SMARCB1 gene in malignant rhabdoid tumors, a highly aggr

92 Germline mutations of the SMARCB1 gene predispose to two distinct tumor syndromes:

93 ic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlat

94 The mechanisms by which SMARCB1 germline mutations predispose to rhabdoid tumors

95 SMARCB1 has also been recognized to be a tumor suppresso

96 ved understanding of the biology and role of SMARCB1 has enabled identification of new targets for sm

97 hromatin remodeling protein SNF5 (encoded by SMARCB1, hereafter called SNF5), which is inactivated in

98 s with characteristic genetic alterations of SMARCB1/hSNF5.

99 Re-expression of SMARCB1 in ATRT cell lines enabled confirmation of our g

100 AT/RTs, we specifically deleted Smarca4 and Smarcb1 in cerebellar granule cell precursors.

101 sing mutation in the SWI/SNF subunit snfc-5 (SMARCB1 in humans) that prevents embryonic lethality in

102 clusion, this study reveals that the loss of SMARCB1 in rhabdoid tumors has specific consequences on

103 s of the nuclear chromatin-remodeling factor SMARCB1 in rhabdoid tumors led to increased phosphorylat

104 hese novel findings support a model in which SMARCB1 inactivation blocks the conversion of growth-pro

105 and TAR explains the mechanism by which INI1/SMARCB1 influences HIV-1 late events and suggests additi

106 SMARCA4 (BRG1) and SMARCB1 (INI1) are tumor suppressor genes that are cruci

107 SMARCB1 is a dependency and required for in vivo growth

108 INI1/hSNF5/BAF47/SMARCB1 is an HIV-1 integrase (IN)-binding protein that

109 Mechanistically, we demonstrate that SMARCB1 is essential for hESC super-enhancer silencing i

110 role as a CNS tumor suppressor, we find that SMARCB1 is essential for neural induction but dispensabl

111 tch/sucrose nonfermentable complex component SMARCB1 is extremely prevalent in pediatric malignant rh

112 summary, we provide functional evidence that SMARCB1 is involved in prednisolone resistance and ident

113 The core subunit SMARCB1 is required for early embryonic survival, and mu

114 We show that SMARCB1 is required for the integrity of SWI/SNF complex

115 SMARCB1 knock-down in neural stem cells (NSCs) led to an

116 SMARCB1 knockdown in human cardiac fibroblasts resulted

117 Orthotopically implanted SMARCB1 knockout (KO) cell lines exhibit increased tumor

118 inhibitor, TTI-101, reduces tumor growth in SMARCB1 KO orthotopic cell line-derived xenografts and a

119 e identified a gene signature generated from SMARCB1 KO tumors that predicts SMARCB1 deficiency in pa

120 ase in apoptosis of human cells with reduced SMARCB1 levels.

121 state and identified an interaction between SMARCB1 loss and neural differentiation pressure that ca

122 To identify potential interactions between SMARCB1 loss and the process of neural development, we i

123 rentiation-inducing ones, and they implicate SMARCB1 loss as a late event in tumorigenic progression.

124 By inducing Smarcb1 loss at later developmental stage in the Schwann

125 Mechanistically, we show that SMARCB1 loss causes increased BRD9 incorporation into SW

126 present new mouse models and show that early Smarcb1 loss causes rhabdoid tumors whereas loss at late

127 ial differences in the downstream effects of SMARCB1 loss depending on differentiation state and iden

128 suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation.

129 SMARCB1 loss has long been observed in many solid tumors

130 Smarcb1 loss in early neural crest was necessary to init

131 RCB1 loss, but the molecular consequences of SMARCB1 loss in extra-cranial tumors have not been compr

132 SMARCB1 loss increases the chromatin accessibility of th

133 Our results provide insight into how SMARCB1 loss might interact with neural development in t

134 ulation and doxorubicin resistance caused by SMARCB1 loss were dependent on the function of SMARCA4,

135 MRTs are driven by SMARCB1 loss, but the molecular consequences of SMARCB1

136 he genetic driver mutation underpinning MRT, SMARCB1 loss, suggest that cells are blocked en route to

137 servations extend across cancers that harbor SMARCB1 loss, which also require expression of the E2 ub

138 ural development, we introduced an inducible SMARCB1 loss-of-function system into human induced pluri

139 fied a promoter SNP that alters the level of SMARCB1 mRNA and protein expression and the binding of P

140 The -228G>T SNP altered SMARCB1 mRNA and protein levels and a positive associati

141 a positive association was found between the SMARCB1 mRNA level and both the -228 genotype and predni

142 ther used an hGFAP-cre allele, which deleted Smarcb1 much earlier and in a wider neural precursor pop

143 Painful SMARCB1 mutant CM, for example, sensitized mice to mecha

144 These data demonstrate the dependency of SMARCB1 mutant MRTs on EZH2 enzymatic activity and porte

145 Notable examples include SMARCB1-mutant cancers, which are highly lethal malignan

146 he basis for selective dependency on PHF6 in SMARCB1-mutant cancers.

147 or 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers.

148 identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR s

149 Here, we performed CRISPR screens in SMARCB1-mutant rhabdoid tumor cells to identify genetic

150 F subcomplex is required for the survival of SMARCB1-mutant RTs.

151 echanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we con

152 (23%) tumours from patients with no germline SMARCB1 mutation exhibited MR.

153 ad previously tested positive for a germline SMARCB1 mutation, this involved loss of the whole, or pa

154 Constitutional SMARCB1 mutations at 22q11.23 have been found in approxi

155 SMARCB1 mutations predispose to rhabdoid tumors and schw

156 Finally, heterozygous CSS-associated SMARCB1 mutations result in dominant gene regulatory and

157 TP53, ATM, ARID1A, AHR, and SMARCB1 mutations were more frequent in PD.

158 either with genomic instability or recurrent SMARCB1 mutations.

159 -independent escapers reveal the presence of Smarcb1-Myc-network-driven mesenchymal reprogramming and

160 After 72 hours of induction of SMARCB1, both SMARCB1-negative PD chordoma cell lines continued to pro

161 sion on cell growth and gene expression, two SMARCB1-negative PD chordoma cell lines with an inducibl

162 s result contrasted with those observed with SMARCB1-negative rhabdoid cell lines in which SMARCB1 re

163 xia induced by SCT with an increased risk of SMARCB1-negative RMC, and shed light into the mechanisms

164 ows that MR is a mechanism of LOH in NF2 and SMARCB1-negative schwannomatosis-related schwannomas, oc

165 a genetic dependency in SMARCB1-perturbed or SMARCB1-null cancers including synovial sarcoma.

166 deling, and that reintroduction of SNF5 into SMARCB1-null cells mimics the primary transcriptional ef

167 o the mechanisms mediating the resistance of SMARCB1-null renal tumors against angiogenesis inhibitio

168 tent with established clinical observations, SMARCB1-null renal tumors were refractory to hypoxia-ind

169 ing (Perturb-seq) of validated hits nominate SMARCB1 of the BAF complex (also known as SWI/SNF) as a

170 with no detectable germline mutation in NF2, SMARCB1 or LZTR1 caused the greatest increase in respons

171 or whether mutations in SWN-related genes, (SMARCB1 or LZTR1) differentially influence pain signalin

172 h genotype-dependent decreased expression of SMARCB1 (P=7.3x10(-22)).

173 c) retains synovial sarcoma character, while Smarcb1 (PBAF- and CBAF-specific) or Pbrm1 (PBAF-specifi

174 vanced into a Phase 1 study in patients with SMARCB1-perturbed and -null tumors.

175 protein 9 (BRD9) is a genetic dependency in SMARCB1-perturbed or SMARCB1-null cancers including syno

176 We show that in the absence of SMARCB1, PHF6 loss disrupts the recruitment and stabilit

177 We found no evidence of MR in SMARCB1-positive schwannomatosis, suggesting that suscep

178 ermentable roles in translation, we assessed SMARCB1 potential roles in translation in rhabdoid tumor

179 Common genetic variation in SMARCB1 previously associated with risk for cardiomyopat

180 (PARP1) as a nuclear protein binding to the SMARCB1 promoter and showed that the -228 SNP significan

181 We identified several SNPs in the SMARCB1 promoter in lymphoblastoid cells from 90 individ

182 n expression and the binding of PARP1 to the SMARCB1 promoter.

183 ), which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young pati

184 These data, together with the expression of SMARCB1 protein in a proportion of cells from schwannoma

185 stinct from that of rhabdoid tumors in which SMARCB1 protein is completely absent in tumor cells.

186 ATRi sensitivity and a reduction in SS18 and SMARCB1 protein levels, but an SSX18-SSX1 Delta71-78 fus

187 that mutant SMARCB1 proteins, like wild-type SMARCB1 protein, retain the ability to suppress cyclin D

188 in cells lacking SMARCB1 suggest that mutant SMARCB1 proteins, like wild-type SMARCB1 protein, retain

189 bute disease-driving mutant proteins such as SMARCB1(Q318X), TDP43(DeltaNLS) and FUS(R495X).

190 MARCB1-negative rhabdoid cell lines in which SMARCB1 re-expression caused the rapid inhibition of gro

191 Taken together, these data establish that SMARCB1 re-expression in PD chordomas alters the reperto

192 Finally, we demonstrated that SMARCB1 re-expression increased cytoplasmic localization

193 profiling experiments further revealed that SMARCB1 re-expression increased global translation and a

194 To determine the impact of SMARCB1 re-expression on cell growth and gene expression

195 s transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferro

196 RNA-sequencing of cell lines after SMARCB1 re-expression showed a down-regulation for rRNA

197 ot result from the inactivating mutations in SMARCB1 (refs.

198 We demonstrate that SMARCB1 regulates both replication and transcription act

199 In this study, we found that SMARCB1 regulates Human Endogenous Retrovirus K (HERV-K,

200 t that in contrast to other studied systems, SMARCB1 represses bivalent genes in hESCs and antagonize

201 ntly, the absence of growth inhibition after SMARCB1 restoration creates a unique opportunity to iden

202 Further, reconstitution of SMARCB1 restored renal tumor sensitivity to hypoxic stre

203 iallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive

204 f the core complex subunits, SNR1 (SNF5/INI1/SMARCB1), results in reproducible wing patterning phenot

205 c assessment of hESC chromatin regulation by SMARCB1 reveals a novel positive regulatory function at

206 The SMARCB1 rs2070458 locus previously associated with incre

207 The SMARCB1 rs2186370 intronic variant (minor allele frequen

208 sensitive to MDM2 and MDM4 inhibition due to SMARCB1's role in regulating p53-depedent apoptotic gene

209 Human and murine PTCL-NOS(SMARCB1-) show similar DNA methylation profiles, with hy

210 letion, which involves another SWI/SNF gene (SMARCB1), shows strong associations with poor chordoma-s

211 ients with meningioma were screened for NF2, SMARCB1, SMARCE1, and SUFU.

212 By depleting BAF subunits SMARCA4 (BRG1) and SMARCB1 (SNF5) as well as MLL4 in cells, we show that BA

213 ric tumors characterized by mutations in the SMARCB1/SNF5/INI1/BAF47 gene.

214 Central testing of tumor and blood for SMARCB1 status was mandated.

215 Ts), which are driven by inactivation of the SMARCB1 subunit of SWI/SNF.

216 orubicin resistance conferred by loss of the SMARCB1 subunit of the SWI/SNF complex was caused by tra

217 Overexpression studies in cells lacking SMARCB1 suggest that mutant SMARCB1 proteins, like wild-

218 found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgr

219 by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or bot

220 r (RT) cell lines mutant for SWI/SNF subunit SMARCB1 to a genome-scale CRISPR-Cas9 depletion screen p

221 In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, we also rep

222 predicted to affect chromatin (BCOR, KDM6A, SMARCB1, TRRAP), immune surveillance (CD58, RFXAP), MAPK

223 Genetic changes in the SMARCB1 tumor suppressor gene have recently been reporte

224 occurs at the genetic locus SNF5 (Ini1/BAF47/Smarcb1), which functions as a subunit of the SWI/SNF ch

225 s in a unique SWI/SNF sub-complex that lacks SMARCB1, which has been considered a core subunit.

226 contain a biallelic inactivating mutation in SMARCB1, which is part of the chromatin remodelling comp

227 luding the N-terminus of the SWI/SNF subunit SMARCB1, which is validated experimentally.

228 with a host chromatin modulator, especially SMARCB1, which upregulates the KSHV ORF50 promoter.

229 Here, we identify a subgroup, PTCL-NOS(SMARCB1-), which is characterized by the lack of the SMA

230 SMARCB1 wild-type renal tumors exhibited lower levels of

231 experiments demonstrated the interaction of SMARCB1 with translation machinery.

232 ACi combination therapies targeting PTCL-NOS(SMARCB1-) within the TME.