ライフサイエンスコーパス: APL

1 APL blasts overexpress annexin II (ANXII), a receptor fo

2 APL externalization occurs in numerous events, and it is

3 APL is a model for oncogene-targeted therapies: all-tran

4 APL is exquisitely sensitive to retinoic acid (RA) and a

5 APL is most commonly caused by a translocation (15:17) a

6 APL is remarkable because of the fortuitous identificati

7 APL neurons contact DPM neurons most densely in the alph

8 APL was chosen as a model disease because of the potenti

9 k circuit showed that Kenyon cells activated APL and APL inhibited Kenyon cells.

10 hort-lived effector cells in response to all APLs but also were characterized by diminished cytokine

11 ized (the latter somewhat less so), allowing APL to differentially inhibit different mushroom body co

12 Aminophospholipid (APL) trafficking across the plasma membrane is a key eve

13 sures externalization of aminophospholipids (APLs) to the outside of the plasma membrane using mass s

14 ghput bisulfite sequencing, we identified an APL-associated hypermethylation at the upstream differen

15 t and intriguing experiments performed in an APL mouse model, they demonstrate that supplementation w

16 heterogeneity prevented the selection of an APL candidate for developing an improved generic gp100 v

17 In the present study, we used an APL mouse model to study ANXII function and the effects

18 r incidence of B-cell ALL/L (IRR = 1.64) and APL (IRR = 1.28); blacks had lower IRs of nearly all AL

19 uclear body reformation, P53 activation, and APL eradication.

20 t showed that Kenyon cells activated APL and APL inhibited Kenyon cells.

21 and axons, and that both activity in APL and APL's inhibitory effect on Kenyon cells are spatially lo

22 ne or both domains decreased APL binding and APL-dependent catalytic activity of nSMase2.

23 omyelocytic leukemia (APL)-derived cells and APL primary cells, and PML-Fas complexes in normal tissu

24 re reduced in PML/RARalpha knock-in mice and APL patient samples.

25 analysis of interactions between nSMase2 and APLs will contribute to our understanding of signaling p

26 In contrast, arsenic, the other potent anti-APL therapy, only induces PML/RARA degradation by specif

27 the absence of antiphospholipid antibodies (APL).

28 f arsenic trioxide in blood cancers (such as APL) has not been seen in solid tumors due to the rapid

29 pirical discoveries that PML-RARa-associated APL is sensitive to both all-trans-retinoic acid (ATRA)

30 -181b as oncomiRs in PML/RARalpha-associated APL, and they reveal RASSF1A as a pivotal element in the

31 tarvation induced the accumulation of barley APL transcripts in both the shoots and roots.

32 pplied to other cell events characterized by APL externalization, including cell division and vesicul

33 for the cooperative activation of nSMase2 by APLs.

34 Disrupting the Kenyon cell-APL feedback loop decreased the sparseness of Kenyon cel

35 copy number analysis of a well-characterized APL mouse model to uncover somatic mutations in Jak1 and

36 However, previously published childhood APL studies have generally analyzed all patients age < 1

37 th newly diagnosed and genetically confirmed APL consecutively treated at a single institution.

38 ade PML/RARA oncoprotein and, together, cure APL.

39 r, mutation of one or both domains decreased APL binding and APL-dependent catalytic activity of nSMa

40 rform additional analyses in patient-derived APL cells with native PML-RARalpha.

41 erm outcome of patients with newly diagnosed APL treated at our institution on 3 consecutive prospect

42 Differentiated APL blasts sorted from uncoupled retinoid-treated mice r

43 of deletion mutants identified two discrete APL binding domains in the N terminus of nSMase2.

44 egradation by arsenic trioxide, an effective APL treatment.

45 l activation, explaining how arsenic elicits APL maturation through PML/RARA degradation.

46 Thus, the molecular species of externalized APL during platelet activation, apoptosis, and energy de

47 In this protocol, externalized APLs are chemically modified by using a cell-impermeable

48 ich produce high levels of the extracellular APL-1 fragment, show an incompletely penetrant temperatu

49 lead to new findings such as biomarkers for APL and additional molecular targets for arsenic trioxid

50 ranscriptional activation is dispensable for APL eradication.

51 Among AML subtypes, survival was highest for APL and AML with inv(16).

52 Thus, differentiation is insufficient for APL eradication, whereas PML/RARA loss is essential.

53 uced by A9/I-A(q), nor are they required for APL stimulation of cytokines.

54 this study, the structural requirements for APL-selective binding of nSMase2 were determined and cha

55 Cells from APL patients showed increased genome-wide DNA methylatio

56 Blocking synaptic output from APL neurons after training disrupts labile memory but do

57 ose promoting phloem formation and function (APL, SUC2).

58 Furthermore, APL contacts MB neurons in the alpha' lobe but makes lit

59 body intrinsic neurons, as well as GABAergic APL neurons and local interneurons of the antennal lobes

60 DR4(+) melanoma patients for different gp100 APLs suggested highly variable TCR usage, even among six

61 is was demonstrated in U937/PR9 cells, human APL cells and transgenic mouse APL cells, in which PMLRA

62 AK1 V658F mutation previously found in human APL and acute lymphoblastic leukemia samples.

63 ogic expression pattern of PML-RARA in human APL patients.

64 eflecting the clinical presentation of human APL.

65 f both humans and mice, and since some human APL samples contain TCR rearrangements and express T lin

66 nsortium on Acute Promyelocytic Leukemia (IC-APL) study.

67 nsortium on Acute Promyelocytic Leukemia (IC-APL) was established to create a network of institutions

68 nsortium on Acute Promyelocytic Leukemia (IC-APL), an initiative of the International Members Committ

69 The IC-APL formulated expeditious diagnostic, treatment, and su

70 The establishment of the IC-APL network resulted in a decrease of almost 50% in earl

71 e show that hypermethylation was acquired in APL in a monoallelic manner.

72 ndrites and axons, and that both activity in APL and APL's inhibitory effect on Kenyon cells are spat

73 n PML-RARalpha, a major etiological agent in APL.

74 e fusion oncogene PML-RARA and treats APL in APL cell and animal models as well as in human patients.

75 to Fas and blocks Fas-mediated apoptosis in APL by forming an apoptotic inhibitory complex with c-FL

76 of arsenic trioxide to trigger apoptosis in APL cells.

77 c differentiation program induced by ATRA in APL.

78 ence of enhanced expression of miR-181a/b in APL patient specimens.

79 stress the key role of PML nuclear bodies in APL eradication by the ATRA/arsenic combination.

80 regulation of the miR-181a/b gene cluster in APL blasts and NB4 leukemia cells upon ATRA treatment as

81 ome toward a more condensed configuration in APL cells; locally, it intrudes RNAPII-associated intera

82 -Myc lymphoma and induced differentiation in APL.

83 re accurately dissecting the early events in APL pathogenesis.

84 ress protein TRIB3 as an important factor in APL disease progression and therapy resistance.

85 In contrast, knock-down of Hdac1 in APL mice led to enhanced survival duration of the leukem

86 Next, inhibiting HK3 in APL cell lines resulted in significantly reduced neutrop

87 cysteinemia may reverse hyperfibrinolysis in APL.

88 s were preferentially DNA hypermethylated in APL cells.

89 Additionally, NTAL-knockdown (NTAL-KD) in APL cell lines led to activation of Ras, inhibition of A

90 n of senescence as a targetable mechanism in APL therapy.

91 o protected from aberrant DNA methylation in APL cells.

92 ain leads to overexpression of the miRNAs in APL.

93 The role of NTAL in APL cell processes, and its association with clinical ou

94 ur data highlights the importance of NTAL in APL cell survival and response to treatment.

95 n chromosome 14q32 are overexpressed only in APL.

96 tients, demonstrating the key role of PML in APL cure.

97 ion induction failure, is a high priority in APL, especially because such events represent a major ca

98 ated with a significantly worse prognosis in APL patients.

99 , the events that cooperate with PML-RARA in APL pathogenesis are not well understood.

100 Jak1 mutations to cooperate with PML-RARA in APL.

101 set of differentially methylated regions in APL was identified.

102 ferentiation syndrome and disease relapse in APL patients treated with AIDA protocols.

103 mportant determinant of clinical response in APL and may offer a therapeutic target for enhancing che

104 benefit conferred by uncoupled retinoids in APL mice is dramatically lower than the one provided by

105 suggested that ANXII plays a pivotal role in APL coagulopathy.

106 kemia, we arrived at an integrative score in APL (ISAPL) and demonstrated its relationship with clini

107 may have a role in exacerbating ER stress in APL cells.

108 nsible for the transcriptional impairment in APLs.

109 otein translation, to ATRA sharply increases APL cell killing to the extent that cures in this diseas

110 o PKA-II in attempts to enhance ATRA-induced APL maturation in a clinical setting.

111 4-d) artificial activation of the inhibitory APL causes increased Kenyon cell odor responses after th

112 gh this fusion oncogene is known to initiate APL in mice, other cooperating mutations, as yet ill def

113 st that PML-RARA requires DNMT3A to initiate APL in mice.

114 Interestingly, APL cells depleted of Hdac3 demonstrated a more differen

115 erative disease that ultimately evolves into APL.

116 plain the less favorable outcome of FLT3-ITD APLs with ATRA-based regimens, and stress the key role o

117 lly rescues therapeutic response in FLT3-ITD APLs, restoring PML/RARA degradation, PML nuclear body r

118 erneuron called the anterior paired lateral (APL) neuron.

119 s and the GABAergic anterior paired lateral (APL) neuron.

120 from the GABAergic anterior paired lateral (APL) neurons.

121 show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through th

122 gnosis in both acute promyelocytic leukemia (APL) and acute myeloid leukemia, we arrived at an integr

123 engraftment of acute promyelocytic leukemia (APL) and myelofibrosis (MF) samples, and identified LICs

124 ome in primary acute promyelocytic leukemia (APL) and the role of promyelocytic leukemia-retinoic aci

125 monitoring in acute promyelocytic leukemia (APL) are available only in the context of conventional a

126 he dynamics of acute promyelocytic leukemia (APL) before and during therapy with regard to disease in

127 nd outcomes in acute promyelocytic leukemia (APL) between developed and developing countries.

128 t component of acute promyelocytic leukemia (APL) bleeding diathesis.

129 ic activity in acute promyelocytic leukemia (APL) but its activity in solid tumors remains to be expl

130 In most acute promyelocytic leukemia (APL) cases, translocons produce a promyelocytic leukemia

131 antly lower in acute promyelocytic leukemia (APL) compared with non-APL patient samples.

132 treatment for acute promyelocytic leukemia (APL) for more than a decade.

133 ) treatment in acute promyelocytic leukemia (APL) has been the paradigm of targeted therapy for oncog

134 Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia tha

135 Acute promyelocytic leukemia (APL) is a hematological malignancy driven by a chimeric

136 Acute promyelocytic leukemia (APL) is a malignancy of the bone marrow, in which there

137 L-RARA-induced acute promyelocytic leukemia (APL) is a morphologically differentiated leukemia, many

138 Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML).

139 A hallmark of acute promyelocytic leukemia (APL) is altered nuclear architecture, with disruption of

140 Acute promyelocytic leukemia (APL) is characterized by a blockade of granulocytic diff

141 Acute promyelocytic leukemia (APL) is characterized by granulopoietic differentiation

142 Acute promyelocytic leukemia (APL) is characterized by the t(15;17) translocation that

143 Acute promyelocytic leukemia (APL) is commonly complicated by a complex coagulopathy.

144 Acute promyelocytic leukemia (APL) is driven by a chromosomal translocation whose prod

145 chemotherapy, acute promyelocytic leukemia (APL) is now the most curable type of leukemia.

146 Acute promyelocytic leukemia (APL) is often associated with activating FLT3 signaling

147 Acute promyelocytic leukemia (APL) is rare in children.

148 se majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combinati

149 Up to 15% of acute promyelocytic leukemia (APL) patients fail to achieve or maintain remission.

150 Acute promyelocytic leukemia (APL) remains the best example of a malignancy that can b

151 patients with acute promyelocytic leukemia (APL) remains unknown because of the paucity of outcome d

152 development of acute promyelocytic leukemia (APL) required DNMT3A.

153 -a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted th

154 osed pediatric acute promyelocytic leukemia (APL) was a phase III historically controlled trial to de

155 Acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloi

156 In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) treatment induces g

157 In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance i

158 In acute promyelocytic leukemia (APL), NTAL depletion from lipid rafts decreases cell via

159 In acute promyelocytic leukemia (APL), repression by the PML-RARalpha oncofusion protein

160 rd of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%.

161 ML/RARA-driven acute promyelocytic leukemia (APL), retinoic acid (RA) induces leukemia cell different

162 e diagnosis of acute promyelocytic leukemia (APL), with t(15;17)(q23;q21.1) in all metaphases.

163 on with Fas in acute promyelocytic leukemia (APL)-derived cells and APL primary cells, and PML-Fas co

164 ha)-associated acute promyelocytic leukemia (APL).

165 ermediate-risk acute promyelocytic leukemia (APL).

166 prises as with acute promyelocytic leukemia (APL).

167 athogenesis of acute promyelocytic leukemia (APL).

168 ewly diagnosed acute promyelocytic leukemia (APL).

169 r treatment of acute promyelocytic leukemia (APL).

170 oncoprotein of acute promyelocytic leukemia (APL).

171 thy present in acute promyelocytic leukemia (APL).

172 causative for acute promyelocytic leukemia (APL).

173 ewly diagnosed acute promyelocytic leukemia (APL).

174 ermediate-risk acute promyelocytic leukemia (APL).

175 nes and drives acute promyelocytic leukemia (APL).

176 e treatment of acute promyelocytic leukemia (APL).

177 y equal IRs of acute promyelocytic leukemia (APL; IRR = 1.08).

178 ewly diagnosed acute promyelocytic leukemia (APL; see figure).

179 Acute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PM

180 ; PML-RARalpha acute promyelocytic leukemia [APL] cells) and Emicro-Myc lymphoma in vitro and in vivo

181 ia and ATRA in acute promyelocytic leukemia [APL]).

182 cell death of acute promyelocytic leukemic (APL) cells by intercepting the degradation of nuclear co

183 Using altered peptide ligands (APLs) displaying high TCR affinities, we show that incre

184 Altered peptide ligands (APLs) were designed to enhance MHC binding and hence T c

185 Altered peptide ligands (APLs) with enhanced binding to MHC class I can increase

186 class II-restricted altered peptide ligands (APLs), which are normally protective in experimental aut

187 ggered T cells with altered peptide ligands (APLs).

188 and association in the presence of linkage (APL; GENECARD) and logistic regression (CATHGEN and aort

189 Sequencing of a mouse APL genome revealed 3 somatic, nonsynonymous mutations r

190 ere observed in 3 out of 14 additional mouse APL samples and 1 out of 150 human AML samples.

191 Kdm6a, also known as Utx) gene, in the mouse APL genome.

192 cells, human APL cells and transgenic mouse APL cells, in which PMLRARalpha recruited c-FLIP(L/S) an

193 Using mouse APL models, we unexpectedly demonstrate that FLT3-ITD se

194 In this study, using NB4 APL cell variants resistant to ATRA-induced differentiat

195 ion from the anterior paired lateral neuron (APL).

196 the ATRA-driven therapeutic response in non-APL AML.

197 translating ATRA/ATO-based strategies to non-APL acute myelocytic leukemia (AML) is currently lacking

198 lectrocardiograms from 113 patients with non-APL acute myeloid leukemia and myelodysplastic syndrome

199 However, among patients with non-APL AML, ATRA-based treatment has not been effective.

200 omyelocytic leukemia (APL) compared with non-APL patient samples.

201 e much more effective than the nonconjugated APL at inhibiting the development of experimental autoim

202 enhanced, compared with the nonpalmitoylated APL, and S-palm APL was taken up more rapidly into dendr

203 hods Patients age 2 to 21 years with de novo APL confirmed by PML-RARalpha polymerase chain reaction

204 of Kenyon cells and decreased activation of APL, with differing relative contributions for different

205 ensation for lack of inhibition (blockade of APL).

206 In this large cohort of APL patients, high white blood cell count emerged as an

207 The known phenotypic constraints of APL could be explained by a combination of differentiati

208 tes fatty acids as molecular determinants of APL that regulate hemostasis.

209 gnized to be insufficient for development of APL, requiring acquisition of cooperating mutations.

210 A total of 1400 patients with a diagnosis of APL between 1992 and 2007 were identified.

211 ression during neutrophil differentiation of APL cell lines.

212 inding, inducing terminal differentiation of APL cells ex vivo or in vivo.

213 Dissection of APL pathogenesis has led to the rediscovery of PML bodie

214 Here we show that pan-neuronal expression of APL-1, the Caenorhabditis elegans ortholog of APP, disru

215 eural circuits, suggesting a broad impact of APL-1 on sensory plasticity in C. elegans.

216 In view of such importance of APL, we have developed an office punching machine crafte

217 is considered in the clinical management of APL.

218 ate that in the Ctsg-PML-RARA mouse model of APL, PML-RARA is expressed in and affects the function o

219 To identify these, we used a mouse model of APL, whereby PML-RARA expressed in myeloid cells leads t

220 Multiple prior mouse models of APL constitutively express PML-RARA from a variety of no

221 the JAK/STAT pathway in the pathogenesis of APL and illustrate the power of whole genome sequencing

222 ylation is implicated in the pathogenesis of APL.

223 which has a key role in the pathogenesis of APL.

224 In the preleukemic phase of APL, Hdac1 counteracts the activity of PML-RAR in (1) bl

225 ink to the clinical hemorrhagic phenotype of APL.

226 r effect on early death and the cure rate of APL.

227 , is present on the extracellular surface of APL cells and is rapidly down-regulated in response to a

228 Treatment of APL blasts with all-trans retinoic acid also did not res

229 ith chemotherapy, the reference treatment of APL, is generally considered to produce similar results

230 f arsenic trioxide (ATO) in the treatment of APL.

231 sulted not only in a better understanding of APL itself, but also carry valuable lessons for other ma

232 rophil differentiation and cell viability of APL cells.

233 rowth inhibitory activities than curcumin on APL cells.

234 ed with the nonpalmitoylated APL, and S-palm APL was taken up more rapidly into dendritic cells and c

235 ase2 was dependent on anionic phospholipids (APLs).

236 In line with the observations in primary APL patient samples, we observed significantly higher HK

237 tis elegans encodes one APP-related protein, APL-1, which is essential for viability.

238 ells from an established transgenic PML-RARA APL mouse model at the orthologous region on chromosome

239 ce retain PML/RARA expression and reinitiate APL in secondary transplants.

240 We suggest that signaling of the released APL-1 fragment modulates multiple metabolic states and t

241 This unifying framework, which reproduces APL, normal progenitor, and differentiated granulocytic

242 tions previously identified in ATO-resistant APL patients are impeded in their ability to become sequ

243 pression of PHF8 resensitizes ATRA-resistant APL cells, whereas its downregulation confers resistance

244 differentiation in ATRA maturation-resistant APL cells.

245 h newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis </= 10 x 10(9)/L).

246 nt of patients with low-to-intermediate-risk APL.

247 with ATRA-CHT in low- and intermediate-risk APL.

248 t in patients with low- or intermediate-risk APL.

249 es virtually all patients with standard-risk APL.

250 ergy depletion (aging) externalized the same APLs in a calcium-dependent manner, and all stimuli exte

251 es ATRA-induced maturation in ATRA-sensitive APL cells (including NB4 cells) and restores it in some

252 Increased MHC binding of several APLs was observed, validating this approach biochemicall

253 acted specifically and directly with several APLs, including phosphatidylserine and phosphatidic acid

254 The modeling shows APL and normal states mutually suppress each other, both

255 Platelet-specific APLs optimally supported tissue factor-dependent coagula

256 ing a potential mechanism for high-stability APLs to enhance immunogenicity and accumulation of T cel

257 We synthesized APLs and corresponding S-palmAPLs and showed that the S-

258 modulates multiple metabolic states and that APL-1 is required throughout development.

259 We demonstrate that APL may emerge from a dynamical endogenous molecular-cel

260 We propose that APL neurons provide widespread inhibition to stabilize a

261 and volumetric calcium imaging to show that APL inhibits Kenyon cells' dendrites and axons, and that

262 Here, we show that APL-1 signaling is dependent on the activity of the FOXO

263 tion of calcium are clearly triggered by the APL A9/I-A(q) stimulation and are required for cytokine

264 at these two cytokines are important for the APL-induced attenuation of arthritis.

265 n conclusion, these data have identified the APL binding domains of nSMase2 for the first time.

266 ), as well as accelerated degradation of the APL-associated fusion oncoprotein PML/retinoic acid rece

267 ed this new potential TF as belonging to the APL (ALTERED PHLOEM DEVELOPMENT) protein family, and we

268 its innate potential, then thiopalmitoylated APLs (S-palmAPLs) should show enhanced protective effect

269 Thus, APL differentiation is a default program triggered by cl

270 targeting of normal PML also contributes to APL response in vivo.

271 ml NB disruption is a central contributor to APL pathogenesis.

272 tand the contribution of molecular events to APL cell differentiation, leukemia-initiating cell (LIC)

273 somatic, nonsynonymous mutations relevant to APL pathogenesis, of which 1 (Jak1 V657F) was found to b

274 These events are not restricted to APL because lymphomagenesis driven by deletion of p53 or

275 were preferentially up-regulated in treated APL cells, supporting the notion that the UPR was a cons

276 Upon treating APL with all-trans retinoic acid and achieving complete

277 d by the fusion oncogene PML-RARA and treats APL in APL cell and animal models as well as in human pa

278 Thus, using APL as a model, we uncover a tolerogenic pathway that ma

279 Conversely, using APLs displaying a decreased TCR affinity tilted our syst

280 Our results demonstrate that site V APLs cross-prime a higher fraction of available T cells,

281 dividual Kenyon cells inhibit themselves via APL more strongly than they inhibit other individual Ken

282 r-dependent coagulation in human plasma, vs. APL with longer or shorter fatty acyl chains.

283 ventually approach the success achieved with APL, CML, and pediatric ALL.

284 e 6A (Kdm6a, also known as Utx) in mice with APL and validated the ability of Jak1 mutations to coope

285 Here we report a patient with APL who developed a mitochondrial myopathy after treatme

286 re well tolerated in pediatric patients with APL and allowed significant reduction in cumulative anth

287 nt after chemotherapy can cure patients with APL by eliminating the stem-like cell population over th

288 ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell c

289 and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid a

290 -based MRD monitoring study on patients with APL treated with a single agent ATO regimen.

291 enrolled low-intermediate risk patients with APL without any DNA-damaging chemotherapy.

292 For SR and HR patients with APL, the overall survival was 98% versus 86% ( P = .003)

293 o may be the first to evaluate patients with APL, to have a major effect on early death and the cure

294 yeloid leukemia, including 231 patients with APL.

295 instituted when ATO is used in patients with APL.

296 elapse risk for both SR and HR patients with APL.

297 uction, and following infection in vivo with APL-expressing bacteria, CD8 RTEs expanded to a greater

298 Adolescents and children age > 4 years with APL treated with ATRA and chemotherapy have outcomes at

299 were essential for nSMase2 to interact with APLs.

300 he clinicoradiological pattern of SS without APL (SSAPL- ) and its midterm prognosis.