ライフサイエンスコーパス: MLL

1 MLL-Af4 activated a self-renewal program in a lineage-de

2 MLL-Af4 induces a B ALL distinct from MLL-AF9 through di

3 MLL-AF4 leukemia is the predominant infant acute leukemi

4 MLL-AF9 and other MLL fusion proteins aberrantly recruit

5 MLL-AF9 expression in long-term hematopoietic stem cells

6 MLL-ENL target loci showed supraphysiological PAF1 bindi

7 MLL-rearranged acute myeloid leukemia (AML) remains a fa

8 TO is highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or

9 1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML.

10 a randomized phase 2-like PDX trial using 13 MLL-rearranged BCP-ALL samples.

11 haematopoietic progenitor stage to develop a MLL-r model capturing early cellular and molecular conse

12 Accordingly, inhibition of CKII in a MLL-AF9 mouse model of leukemia delayed leukemic progres

13 e expression patterns, including an aberrant MLL signature.

14 se model of AML, the loss of Cdc42 abrogates MLL-AF9-induced AML development.

15 In addition, MLL-FP driven acute myeloid leukemia (AML) in mice is of

16 orable acute GVHD and GVL properties against MLL-AF9-eGFP cells.

17 the development of therapies for aggressive MLL leukemia and perhaps for other cancers caused by tra

18 provided a constitutive PAF1 tether allowing MLL fusions to circumvent H3 competition.

19 Although MLL/COMPASS (complex of proteins associated with Set1) f

20 a genome-scale loss-of-function screen in an MLL-AF4-positive acute leukaemia cell line, we identify

21 uced LSC differentiation and depletion in an MLL-AF9-driven mouse model of AML, leading to reduction

22 Using an MLL-AF9 murine leukemia model and serial transplantation

23 al targeted therapy for AML patients with an MLL rearrangement and an FLT3-ITD.

24 sequencing) analyses showed that MLL-AF4 and MLL-ENL fusions directly bound to the BCL6 promoter and

25 Here, we have shown that MLL-ENL and MLL-AF10 constitutively activate transcription by aberra

26 in relapsed acute lymphoblastic leukemia and MLL-rearranged acute leukemia.

27 Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic

28 The interaction of menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and provides a potenti

29 rotein-protein interaction between menin and MLL fusion proteins that plays an important role in acut

30 ex contributes to the association of MLL and MLL-fusion multiprotein complexes with the chromatin.

31 The N-terminus of MLL and MLL-fusions form a complex with lens epithelium-derived

32 nt in models of human and murine NPM1mut and MLL-r leukemias harboring an FLT3 mutation.

33 y for treatment of NPM1-mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias.

34 n genes such as PML-RARA, RUNX1-RUNX1T1, and MLL-AF9.

35 DNMT3A is dispensable for RUNX1-RUNX1T1- and MLL-AF9-driven self-renewal.

36 In human xenograft and MLL-AF9 mouse leukemia models, MTHFD2 suppression decrea

37 ed using a relative quantification approach (MLL as reference system).

38 volvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription

39 ia gene (MLL) rearrangements (MLL-r) such as MLL-AF4 are a major cause of incurable acute lymphoblast

40 c stem cells, and decreased MLL occupancy at MLL target genes.

41 eveloped and optimized a new AlphaLISA-based MLL HMT functional assay to facilitate the functional ev

42 suggesting a positive feedback loop between MLL and BCL6.

43 ced leukemias, preferentially at gene bodies.MLL-AF9-induced leukemogenesis showed much less pronounc

44 stem cells (CSCs) including those driven by MLL fusions, here we show that transcriptional memory fr

45 When driven by MLL-AF9, leukemia cells in the adult microenvironment su

46 hronic transplantation of leukemia driven by MLL/KMT2A translocations to investigate the contribution

47 for the treatment of acute leukemia carrying MLL fusion (MLL leukemia).

48 for the treatment of acute leukemia carrying MLL fusion (MLL leukemia).

49 ;11 and MOLM-13 leukemia cell lines carrying MLL fusion with IC(50) values of 25 and 55 nM, respectiv

50 Cell lines carrying MLL rearrangements were selectively responsive to VTP504

51 Patients carrying MLL-FPs have very few cooperating mutations, making MLL-

52 mosomal translocations producing a chimaeric MLL oncogene give rise to a highly aggressive acute leuk

53 e mRNA level from the wild-type and chimeric MLL alleles, the chimeric protein is more stable.

54 neage leukemia (MLL) to AF4, the most common MLL-fusion partner.

55 In contrast, MLL-Af4 cells, which were fully oncogenic under lymphoid

56 ly known as an RNA splicing factor, controls MLL complex-mediated transcriptional initiation.

57 the mixed-lineage leukemia gene (MLL) create MLL-fusion proteins, which could drive both acute lympho

58 olecule BIM, while BCL6 was required to curb MLL-induced expression of BIM.

59 the hematopoietic stem cells, and decreased MLL occupancy at MLL target genes.

60 rease in yH2AX nuclear foci in Mof-deficient MLL-AF9 tumor cells.

61 activated receptor-1), in Runx1/Cbfb-deleted MLL-AF9 cells.

62 Hoxa9 that is highly enriched in LSK-derived MLL-CSCs and helps sustain leukemic self-renewal.

63 Suppression of Hoxa9 sensitizes LSK-derived MLL-CSCs to beta-catenin inhibition resulting in abolish

64 beta-catenin/Hoxa9 functions in LSK-derived MLL-CSCs.

65 Despite MLL proteins being postulated as essential for normal de

66 his review provides an overview of different MLL-FP mouse model systems and discusses how well they h

67 bout the specific functions of the different MLL lysine methyltransferases.

68 rmation and for the expression of downstream MLL-regulated genes such as HOXA9 and MEIS1 In light of

69 NIN and LEDGF/p75 are required for efficient MLL-fusion-mediated transformation and for the expressio

70 DX) models derived from patients with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblasti

71 with the BH3-mimetic ABT-199 in eradicating MLL-rearranged B-ALL cells.

72 and histone demethylases in AML, especially MLL-rearranged leukaemia.

73 Cells expressing MLL-AF9 efficiently developed AML in NSGS mice.

74 stem and progenitor cells (HSPCs) expressing MLL-AF9 or MLL-Af4 into immunodeficient NSGS mice, which

75 subset of low HIF1alpha/low MEIS1-expressing MLL-rearranged leukemia cells.

76 regulator of HSC function, which facilitates MLL-AF9-mediated leukemic disease in mice.

77 s demonstrating that MLL1 is dispensable for MLL-fusion-mediated leukemogenesis.

78 els, that endogenous MLL1 is dispensable for MLL-rearranged leukemia.

79 several genes including those essential for MLL-rearranged leukemogenesis, such as DOT1L and SETD1A.

80 ated an inducible transgenic mouse model for MLL-AF9-driven leukemia.

81 CND1 expression predicts worse prognosis for MLL fusion AMLs.

82 o discover cytotoxic compounds selective for MLL-rearranged leukemia identified CCI-006 as a novel in

83 tion is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia.

84 t to chromatin as an effective treatment for MLL-fusion leukaemia".

85 MLL-Af4 induces a B ALL distinct from MLL-AF9 through differential genomic target binding of t

86 l and induces apoptosis of primary LSCs from MLL-rearranged AML patients in vitro and in vivo in xeno

87 tment of acute leukemia carrying MLL fusion (MLL leukemia).

88 tment of acute leukemia carrying MLL fusion (MLL leukemia).

89 partners, identifying the novel fusion gene MLL-DIAPH2 in the process.

90 s involving the mixed-lineage leukemia gene (MLL) create MLL-fusion proteins, which could drive both

91 Mixed lineage leukemia gene (MLL) rearrangements (MLL-r) such as MLL-AF4 are a major

92 X) of pediatric mixed-lineage leukemia gene (MLL)-rearranged ALL were established in NOD.Cg-Prkdc(sci

93 ixed-lineage leukemia 1 (MLL1) gene generate MLL chimeras that drive the pathogenesis of acute myeloi

94 ant BCL6 expression in B-ALL cells, germline MLL was required to up-regulate Bcl6 in response to phys

95 nt of acute myeloid leukemia (AML) harboring MLL translocations.

96 rowth in human leukemia cell lines harboring MLL translocations and is >40 times better than the prev

97 of CDK inhibitors in AML patients harboring MLL fusion proteins.

98 s (iPSCs) from AML patient samples harboring MLL rearrangements and found that they retained leukemic

99 er cells and at the translocation 'hotspot', MLL.

100 c ablation of CDC42 in both murine and human MLL-AF9 (MA9) cells decreased survival and induced diffe

101 blocked the growth of both murine and human MLL-AF9 leukemia cell lines.

102 ntly impairs propagation of murine and human MLL-rearranged leukemia in vitro and in vivo.

103 Targeting wild-type MLL degradation impedes MLL leukemia cell proliferation, and it downregulates a

104 In MLL-ENL leukemia, the neonatal microenvironment potentia

105 ted the cell-dose-dependent role of PAR-1 in MLL-AF9 leukemia: PAR-1 inhibited rapid leukemic prolife

106 Using the DOT1L inhibitor EPZ-5676 in MLL-AF4 leukemia cells, we show that H3K79me2/3 is requi

107 Highlighting the central role of BCL6 in MLL-rearranged B-ALL, conditional deletion and pharmacol

108 n accessibility, and direct IKZF2 binding in MLL-AF9 LSCs demonstrate that IKZF2 regulates a HOXA9 se

109 d sensitivity to vincristine chemotherapy in MLL-rearranged B-ALL patient samples.

110 onal role at a subset of active enhancers in MLL-AF4 leukemia cells.

111 73 (R972/973), and its oncogenic function in MLL-r ALL cells is FLT3 methylation dependent.

112 ere, we demonstrate elevated PRMT1 levels in MLL-r ALL cells and show that inhibition of PRMT1 signif

113 c target for selectively eliminating LSCs in MLL-rearranged AML.

114 present a critical pathogenetic mechanism in MLL-rearranged B-ALL and support IGF2BP3 and its cognate

115 ist on the requirement for wild-type MLL1 in MLL-rearranged leukemia.

116 also observe an unexpected role for MLL2 in MLL-rearranged leukemia cells and identify potential the

117 e splicing, is consistently overexpressed in MLL-rearranged leukemias.

118 vely correlated with Alox5 overexpression in MLL-AF9-leukemic blast cells; inhibition of the above si

119 sensitizer, with a therapeutic potential, in MLL-rearranged AML.

120 1 expression and attenuated proliferation in MLL-AF9 cells.

121 d that ALOX5 is especially down-regulated in MLL-rearranged AML, via transcription repression mediate

122 uiescence, and promoting LSC self-renewal in MLL-rearranged AML.

123 72 triggers immune-inflammatory responses in MLL-AF9 cells including upregulation of Hif1alpha and PD

124 de the basis for a new therapeutic target in MLL-rearranged leukemia and act as further validation of

125 ht the relevance of MLL2 as a drug target in MLL-rearranged leukemia and suggest its broader signific

126 s beta-catenin-independent transformation in MLL-CSCs derived from hematopoietic stem cell (HSC)-enri

127 viously undescribed metabolic variability in MLL-rearranged leukemia that may contribute to the heter

128 ificant chromosomal rearrangements including MLL translocations to known and unknown partners, identi

129 l precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALL

130 some acute myeloid leukemia types, including MLL-AF9(+) MOLM-14 cells, in a biphasic manner by autocr

131 Inducible expression of Bcl6 increased MLL mRNA levels, which was reversed by genetic deletion

132 rt sites, interacts with menin, and inhibits MLL complex assembly, resulting in decreased H3K4me3 and

133 ogical insights each model has provided into MLL-FP leukemogenesis.

134 ed a novel small molecule that rapidly kills MLL-rearranged leukemia cells by targeting a metabolic v

135 e acute leukemias, notably those with KMT2A (MLL) gene rearrangements.

136 ty over the HL-60 leukemia cell line lacking MLL fusion.

137 is catalyzed by the mixed lineage leukaemia (MLL) family of histone methyltransferases including MLL1

138 The mixed lineage leukaemia (MLL) family of proteins (including MLL1-MLL4, SET1A and

139 Mixed lineage leukemia (MLL) family histone methyltransferases are enzymes that

140 3 and is involved in Mixed Lineage Leukemia (MLL) fusion leukemogenesis; however, its role in prostat

141 enesis driven by the mixed lineage leukemia (MLL) fusion oncogene MLL-AF9.

142 ations involving the mixed lineage leukemia (MLL) gene fuse it in frame with multiple partner genes c

143 ranslocations of the mixed lineage leukemia (MLL) gene occur in 60% to 80% of all infant acute leukem

144 earrangements of the mixed lineage leukemia (MLL) gene occur in ~10% of B-cell acute lymphoblastic le

145 The mixed-lineage leukemia (MLL) gene often fuses with ENL and AF10 family genes in

146 rearrangement of the mixed lineage leukemia (MLL) gene with CD19 CAR-T cells.

147 ranslocations of the mixed-lineage leukemia (MLL) gene with various partner genes result in aggressiv

148 , a component of the mixed-lineage leukemia (MLL) histone methyltransferase complex, and transcriptio

149 It is fused to mixed-lineage leukemia (MLL) in leukemia, and missense mutations have been ident

150 internal-tandem and mixed-lineage leukemia (MLL) partial-tandem duplications, and clinically signifi

151 ibition of the menin-mixed lineage leukemia (MLL) protein-protein interaction is a promising new ther

152 ) and block the WDR5-mixed lineage leukemia (MLL) protein-protein interaction.

153 ylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regula

154 Mixed lineage leukemia (MLL) represents a genetically distinct and aggressive su

155 4;11)(q21;q23) fuses mixed-lineage leukemia (MLL) to AF4, the most common MLL-fusion partner.

156 ients suffering from mixed lineage leukemia (MLL)-rearranged leukemia remain below 50% and more targe

157 tain cancers such as mixed-lineage leukemia (MLL)-rearranged leukemias.

158 and therapy-induced mixed lineage leukemia (MLL).

159 d levels of MEIS1, an important leukemogenic MLL target gene that plays a role in regulating metaboli

160 GVL against 2 acute myeloid leukemia lines (MLL-AF9-eGFP and C1498-luciferase).

161 have very few cooperating mutations, making MLL-FP driven leukemias ideal for animal modeling.

162 sing preclinical studies with XPO1 and menin-MLL inhibitors.

163 A new orally bioavailable Menin-MLL inhibitor (VTP-50469) appears to promote their diffe

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

165 Combining menin-MLL inhibition with specific small-molecule kinase inhib

166 fter pharmacological inhibition of the menin-MLL complex revealed specific changes in gene expression

167 ructure-property relationships for the menin-MLL inhibitors, demonstrates challenges in optimizing in

168 ss of small-molecule inhibitors of the menin-MLL interaction (hereafter called menin inhibitors).

169 Targeting the menin-MLL protein-protein interaction is a new therapeutic str

170 e is known about cellular factors modulating MLL complex activity.

171 x5 was further confirmed in human and murine MLL-rearranged AML cell models in vitro, as well as in t

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

173 ication approaches, showing that the nuclear MLL system performed better than the mitochondrial HAKE

174 ion and apoptosis in a subset (7/11, 64%) of MLL-rearranged leukemia cell lines within a few hours of

175 manner, showing the leukemogenic activity of MLL-Af4 was interlinked with lymphoid lineage commitment

176 ems designed to explore different aspects of MLL-FP leukemogenesis.

177 is complex contributes to the association of MLL and MLL-fusion multiprotein complexes with the chrom

178 bute to the strong B-cell ALL association of MLL-AF4 leukemia observed in the clinic.

179 Relapse remains the main cause of MLL-rearranged (MLL-r) acute lymphoblastic leukemia (ALL

180 early cellular and molecular consequences of MLL-ENL expression based on a clear clonal relationship

181 The lineage decision of MLL-fusion leukemia is influenced by the fusion partner

182 ge of MLL1 results in the destabilization of MLL.

183 s of Runx1/Cbfb inhibited the development of MLL-AF9-induced AML.

184 LSC frequency and caused differentiation of MLL-AF9- and homeobox A9-driven (HOXA9-driven) leukemias

185 eaved MLL1 can result in the displacement of MLL chimeras from chromatin in leukemic cells.

186 Dysregulation of MLL complex-mediated histone methylation plays a pivotal

187 with MS023 treatment enhanced elimination of MLL-r ALL cells relative to PKC412 treatment alone in pa

188 nstrate that AMPK maintains the epigenome of MLL-rearranged AML by linking acetyl-coenzyme A (CoA) ho

189 a identified CCI-006 as a novel inhibitor of MLL-rearranged and CALM-AF10 translocated leukemias that

190 ostnatal hematopoiesis and the initiation of MLL leukemogenesis.

191 opoiesis but essential for the initiation of MLL-mediated leukemia.

192 2 in a murine model decreased the latency of MLL-AF9-induced leukemia and caused resistance to cytara

193 e self-renewal ability and leukemogenesis of MLL-Af4 myeloid cells could contribute to the strong B-c

194 Loss of MLL binding led to changes in gene expression, different

195 ated a pronounced effect in a mouse model of MLL leukemia.

196 ditional deletion of Mof in a mouse model of MLL-AF9-driven leukemogenesis reduced tumor burden and p

197 Here we use a well-defined model of MLL-rearranged acute myeloid leukaemia (AML) to demonstr

198 from genetically engineered mouse models of MLL-AF9-driven acute myeloid leukemia (AML).

199 mia development induced by a small number of MLL-AF9 leukemia stem cells (LSCs) in vivo.

200 mplexes and inhibited chromatin occupancy of MLL at select genes.

201 it determined the transforming potential of MLL-ENL.

202 PAR-1 increased the adherence properties of MLL-AF9 cells and promoted their engraftment to bone mar

203 S-5272, causes dramatic tumor regressions of MLL-AF9-driven AML in vivo with a tolerable toxicity.

204 complex assembly and activity regulation of MLL family methyltransferases, and also suggest a univer

205 for survival, quiescence and self-renewal of MLL-AF9 (MA9)-transformed leukemia stem cells (LSCs) in

206 ch to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies and pr

207 ment of aggressive leukemia as the result of MLL translocations.

208 Stabilization of MLL provides us with a paradigm in the development of th

209 DM16 is required for specific suppression of MLL fusion protein-induced leukemogenesis both in vitro

210 lone had a significant impact on survival of MLL-AF9-transformed cells, and additional Mll1 loss furt

211 The N-terminus of MLL and MLL-fusions form a complex with lens epithelium-

212 eveloping a new therapy for the treatment of MLL leukemia.

213 a new class of therapy for the treatment of MLL leukemia.

214 We found treatment of MLL-fusion leukaemia cells (MV4;11 cell line) with the B

215 BCL6 as a novel target for the treatment of MLL-rearranged B-ALL.

216 raction as novel target for the treatment of MLL-rearranged leukemia.

217 ex and DOT1L for more effective treatment of MLL-rearranged leukemia.

218 Treatment of MLL-rearranged leukemic cells with dinaciclib resulted i

219 arkable anticlonogenic cell growth effect on MLL-AF9 human leukemia cells.

220 ing an acute myeloid leukemia (AML) oncogene MLL-AF9, we reveal that the cell cycle rate heterogeneit

221 mixed lineage leukemia (MLL) fusion oncogene MLL-AF9.

222 Oncogenic MLL fusions strongly induced transcriptional activation

223 ent of malignant transformation by oncogenic MLL fusions and identified BCL6 as a novel target for th

224 While oncogenic MLL fusions strongly induced aberrant BCL6 expression in

225 ogenitor cells (HSPCs) expressing MLL-AF9 or MLL-Af4 into immunodeficient NSGS mice, which strongly p

226 with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblastic leukemia (ALL) showed dramatic

227 peutic strategy for patients with NPM1mut or MLL-r leukemia and concurrent FLT3 mutation.

228 MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regula

229 expression was also variable in a pediatric MLL-rearranged ALL patient dataset, highlighting the exi

230 tion in human leukemia cell lines possessing MLL-AF9 translocations.

231 Lessons learned from past and present MLL-FP models may serve as a paradigm for designing more

232 artner genes creating novel fusion proteins (MLL-FPs) that cause aggressive acute leukemias in humans

233 ressed in mixed lineage leukemia-rearranged (MLL-rearranged) B-acute lymphoblastic leukemia (B-ALL),

234 se remains the main cause of MLL-rearranged (MLL-r) acute lymphoblastic leukemia (ALL) treatment fail

235 ial therapeutic strategy for MLL-rearranged (MLL-r) leukemia.

236 of NPM1-mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias.

237 lineage leukemia gene (MLL) rearrangements (MLL-r) such as MLL-AF4 are a major cause of incurable ac

238 ent of patients with relapsed and refractory MLL-B-ALL who receive CD19 CAR-T-cell therapy.

239 In vitro studies identified SET1/MLL histone methyltransferases as redox sensitive units

240 are two closely related members of the SET1/MLL family of histone H3K4 methyltransferases and are re

241 complex represents the prototype of the SET1/MLL family of methyltransferases that controls gene tran

242 e HAT activity of MOF is required to sustain MLL-AF9 leukemia and may be important for multiple AML s

243 s the impact of different reference systems (MLL and HAKE) in the absolute-relative and relative quan

244 on represents a promising strategy to target MLL-r ALL cells.

245 Molecularly, we propose that MLL-AF9 preserves gene expression of the cellular states

246 Here we show that MLL fused to murine Af4, highly conserved with human AF4

247 We show that MLL-AF9 leukemia cells maintain cell polarity in the con

248 -throughput sequencing) analyses showed that MLL-AF4 and MLL-ENL fusions directly bound to the BCL6 p

249 Here, we have shown that MLL-ENL and MLL-AF10 constitutively activate transcripti

250 The MLL-AF4 (MA4) fusion gene is the genetic hallmark of an

251 Although the MLL-CHD fusion protein failed to immortalize HSPCs in my

252 etoposide-induced chromosomal breaks at the MLL and RUNX1 loci.

253 n a syngeneic murine AML model driven by the MLL-AF9 oncogenic fusion protein.

254 These data corroborate the MLL-LEDGF/p75 interaction as novel target for the treatm

255 g wild-type MLL protein, which displaces the MLL chimera from some of its target genes and, therefore

256 37) Tethering the small compound 1-10 in the MLL-binding pocket of the CBP-KIX domain weakened BMAL1

257 ifferentiation of leukemic stem cells in the MLL-translocated molecular subtype of acute myeloid leuk

258 of 0.90 nM (Ki value <1 nM) and inhibits the MLL H3K4 methyltransferase (HMT) activity with an IC50 v

259 suggested that the G-region emerges near the MLL-binding pocket, further supporting a role of this po

260 IP-depleted cells demonstrated a loss of the MLL and HOXA9 leukemia stem cell program.

261 ates a specific group of target genes of the MLL chimeras and their oncogenic cofactor, the super elo

262 lity, and results in the displacement of the MLL chimeras from chromatin.

263 onale for the simultaneous inhibition of the MLL fusion-AF4 complex and DOT1L for more effective trea

264 a carrying chromosomal translocations of the MLL gene.

265 as marked by oncogenic rearrangements of the MLL gene.

266 opoulou et al. report that expression of the MLL-AF9 fusion results in acute myelogenous leukemia (AM

267 and the lncRNA Hottip/HOTTIP, members of the MLL/COMPASS-like H3K4 methylases, which regulate chromat

268 nary complex with BMAL1, indicating that the MLL-binding pocket is important for KIX-BMAL1 interactio

269 The fact that the MLL-FP is the main driver mutation has allowed for a wid

270 Absolute quantification using the MLL nuclear system has been demonstrated as appropriate

271 mutations favoring PAF1 binding, whereas the MLL moiety provided a constitutive PAF1 tether allowing

272 tudies, the molecular mechanisms whereby the MLL complexes recognize histone H3K4 within nucleosome c

273 relieves the cellular oncogenic addiction to MLL chimeras.

274 ecruitment of the transcription machinery to MLL target genes.

275 F inhibitors as a targeted approach to treat MLL-rearranged leukemias.

276 Targeting wild-type MLL degradation impedes MLL leukemia cell proliferation,

277 ons in regulating the stability of wild-type MLL in response to interleukin-1 signaling.

278 urine leukemia through stabilizing wild-type MLL protein, which displaces the MLL chimera from some o

279 These findings uncover MLL-dependent transcriptional activation of BCL6 as a pr

280 wareness of the biologic features underlying MLL-rearranged leukemia, targeted therapies for this leu

281 Thus, defining mechanisms underlying MLL-r ALL maintenance is critical for developing effecti

282 In addition, unresponsive MLL-rearranged leukemia cells expressed increased levels

283 ion sensitized an intrinsically unresponsive MLL-rearranged leukemia cell to CCI-006, indicating that

284 The unresponsive MLL-rearranged leukemia cells did not undergo mitochondr

285 son to the sensitive cells, the unresponsive MLL-rearranged leukemia cells were characterized by a mo

286 his signature, SOCS2, was investigated using MLL-AF9 and Flt3-ITD/NPM1c driven mouse models of AML.

287 l models in vitro, as well as in the in vivo MLL-rearranged AML BMT model coupled with treatment of "

288 esents the most potent inhibitor of the WDR5-MLL interaction reported to date, and further optimizati

289 proteins regardless of matrix stiffness when MLL-AF9 and BCR-ABL are overexpressed in K-562 and MOLM-

290 ly and specifically upregulated in AMLs with MLL translocations.

291 In vivo treatment of leukemic animals with MLL-r FLT3mut leukemia reduced leukemia burden significa

292 eatment option for infants and children with MLL-rearranged BCP-ALL who have a poor outcome when trea

293 RDM16 by DNA methylation is concomitant with MLL-AF9-induced leukemic transformation.

294 vator complex that makes direct contact with MLL fusion proteins and is involved in AML, however, its

295 Multiple mice engrafted with MLL-r ALL remained disease free for more than 1 year aft

296 ys an important role in acute leukemias with MLL translocations.

297 erentiation, in particular, in patients with MLL translocations.

298 n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML.

299 improved survival in mice transplanted with MLL-AF9-positive leukemic stem cells by modulating AKT a

300 -BET151 efficacy in a disseminated xenograft MLL mouse model, whereas the original study reported inc