ライフサイエンスコーパス: JMML

1 JMML arises from clonal expansion of a hematopoietic ste

2 JMML has been extensively modeled in mice expressing the

3 JMML is categorized as an overlap myelodysplastic syndro

4 JMML leukemogenesis is linked to a hyperactivated RAS pa

5 JMML pathobiology is characterized by constitutive activ

6 JMML remains a disease for which few curative therapies

7 JMML was characterized by young age at onset and promine

8 uently identified CBL mutations in 27 of 159 JMML samples.

9 al hearts, whereas those expressing an SHP-2 JMML-associated mutation do not.

10 utations in PTPN11 were detected in 16 of 49 JMML specimens from patients without NS, but they were l

11 the entire coding region for mutations in 51 JMML specimens and in selected exons from 60 patients wi

12 A JMML mouse model, achieved through homozygous deletion o

13 lly identical reconstituted mice developed a JMML-like disorder, but only a subset went on to develop

14 monstrated that mutations in Ptpn11 induce a JMML-like MPN through cell-autonomous mechanisms that ar

15 Shp2(D61G) mutant zebrafish recapitulated a JMML-like MPN phenotype, including myeloid lineage hyper

16 sensitivity of leukemic progenitors from all JMML progenitors and some CMML patients to the fusion to

17 btypes, JMML in neurofibromatosis type 1 and JMML in children with CBL syndrome, are defined by germl

18 expansion of a hematopoietic stem cell, and JMML cells and murine Nf1-/- hematopoietic cells are hyp

19 SGS mice support the development of CMML and JMML disease-initiating and mature leukemic cells in viv

20 monstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplant

21 Engraftment of CMML and JMML resulted in overt phenotypic abnormalities and leth

22 juvenile myelomonocytic leukemia (JMML) and JMML-like myeloproliferative neoplasm (MPN) associated w

23 Childhood subtypes of MDS and JMML represent distinct entities with distinct clinical

24 had no additional adverse effect on MDS and JMML.

25 e disease course in patients with NS/MPD and JMML.

26 used to study an unusual child with NF1 and JMML who subsequently had T-cell lymphoma.

27 oding the most prevalent Noonan syndrome and JMML mutations into Xenopus embryos.

28 rasG12D/G12D-expressing HSCs, which serve as JMML/MP-CMML-initiating cells, show strong hyperactivati

29 f p110alpha in mice with KRASG12D-associated JMML markedly delayed their death.

30 t understanding the molecular biology behind JMML and identified a previously unrecognized molecular

31 les showed no consistent differences between JMML, CMML, and normal light density or CD34(+) bone mar

32 hit, oncogenic Kras mutations initiate both JMML and TLL/L, but with different efficiencies.

33 Clinically, JMML manifests as monocytic leukocytosis, splenomegaly w

34 ncofetal protein overexpressed by clonogenic JMML cells, may serve as a target of an antitumor immune

35 s associated with not only preleukemic CMML, JMML, and other MPN, but also progression to AML, sugges

36 cal inhibition of MEK kinase in iPSC-derived JMML cells reduced their GM-CSF independence, providing

37 have a markedly increased risk of developing JMML, we have previously developed a mouse model of JMML

38 sG12D mouse model that reproducibly develops JMML-like disease.

39 d the remaining animals continued to display JMML/MP-CMML-like phenotypes.

40 l survival rates at 6 years were as follows: JMML, 31% +/- 26%; RA and RAEB, 29% +/- 16%; RAEB-T, 30%

41 uld be an effective therapeutic strategy for JMML and AML.

42 ed MPN and may represent a future target for JMML therapies.

43 The optimum treatment for JMML remains unknown.

44 perhaps indicating a potential treatment for JMML.

45 ipheral blood and bone marrow collected from JMML patients harboring Cbl or other known JMML-associat

46 es of HSPCs with SHP2 mutations derived from JMML patients and a novel NS zebrafish model.

47 sh embryos and bulk sequencing of HSPCs from JMML patients revealed an overlapping inflammatory gene

48 Distinguishing RALD from JMML and CMML has implications for clinical care and pro

49 Furthermore, JMML progenitors express higher levels of c-JUN than hea

50 yze gamma-globin(+), but not gamma-globin(-) JMML cells in an A2-restricted manner.

51 Human JMML and murine Nf1-deficient cells are hypersensitive t

52 ood or bone marrow cells obtained from human JMML patients and in assays measuring the potential of r

53 f BTK or p110delta in a mouse model of human JMML equally reduces monocytosis and splenomegaly; howev

54 ng a severe form of MPD that resembles human JMML.

55 mphocyte infusions have clinical activity in JMML, T-cell-mediated immunotherapy could provide a nonr

56 days (equivalent to an early juvenile age in JMML patients).

57 F signaling may be of therapeutic benefit in JMML, our data also demonstrate aberrant proliferation o

58 in tyrosine phosphatase Shp-2, are common in JMML.

59 hway as a target for rational drug design in JMML.

60 ctivity and was only moderately effective in JMML assays and in cancer chemoprevention assays.

61 it has not been comprehensively evaluated in JMML.

62 mutations are largely mutually exclusive in JMML, which suggests that mutant SHP-2 proteins deregula

63 mon and most active Ptpn11 mutation found in JMML and acute leukemias.

64 The cellular hierarchy in JMML is poorly characterized, including the identity of

65 c-Cbl may represent key molecular lesions in JMML patients without RAS/PTPN11 lesions, suggesting ana

66 SHP2, NF-1, KRAS, and NRAS are mutated in JMML patients, leading to aberrant regulation of RAS sig

67 scovery of nearly 90% of driver mutations in JMML, all of which thus far converge on the Ras signalin

68 Outcomes in JMML vary markedly from spontaneous resolution to rapid

69 e a role in deregulating this key pathway in JMML.

70 us, we show that DNA methylation patterns in JMML are predictive of outcome and can identify the pati

71 firmed the involvement of deregulated Ras in JMML pathogenesis.

72 76 was the most commonly affected residue in JMML (n = 45), with the Glu76Lys alteration (n = 29) bei

73 pendence in CMML, consistent with results in JMML.

74 eral hematologic abnormalities often seen in JMML patients, in part by reducing the burden of leukemi

75 icant inhibitory effects would still show in JMML cultures.

76 suggest that inhibiting GM-CSF signaling in JMML/MP-CMML patients might alleviate disease symptoms b

77 a hallmark of a novel fetal-like subgroup in JMML.

78 e elevation in fetal hemoglobin seen in JCML/JMML is a result of primary involvement of erythroid pro

79 kemia/juvenile myelomonocytic leukemia (JCML/JMML).

80 iesis, (2) confirm the clonal nature of JCML/JMML, (3) suggest that the elevation in fetal hemoglobin

81 m JMML patients harboring Cbl or other known JMML-associated mutations.

82 specially juvenile myelomonocytic leukaemia (JMML), a childhood myeloproliferative neoplasm (MPN).

83 mutated in juvenile myelomonocytic leukemia (JMML) and acute myeloid leukemia (AML).

84 h those of juvenile myelomonocytic leukemia (JMML) and chronic myelomonocytic leukemia (CMML), includ

85 n sporadic juvenile myelomonocytic leukemia (JMML) and JMML-like myeloproliferative neoplasm (MPN) as

86 mia (ALL), juvenile myelomonocytic leukemia (JMML) and LEOPARD syndrome frequently carry a second, so

87 isposed to juvenile myelomonocytic leukemia (JMML) and lethally irradiated mice given transplants wit

88 including juvenile myelomonocytic leukemia (JMML) and T-cell lymphoblastic leukemia/lymphoma (TLL/L)

89 evalent in juvenile myelomonocytic leukemia (JMML) and the myeloproliferative variant of chronic myel

90 (CMML) and juvenile myelomonocytic leukemia (JMML) are myelodysplastic syndrome (MDS)/myeloproliferat

91 allmark of juvenile myelomonocytic leukemia (JMML) but has not been systematically shown in the relat

92 ndrome and juvenile myelomonocytic leukemia (JMML) have germline mutations in PTPN11 and that somatic

93 Juvenile myelomonocytic leukemia (JMML) is a disease that occurs in young children and is

94 Juvenile myelomonocytic leukemia (JMML) is a lethal disease of young children characterize

95 Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder of childhood caus

96 Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder that predominantl

97 Juvenile myelomonocytic leukemia (JMML) is a pediatric myelodysplastic syndrome that is as

98 Juvenile myelomonocytic leukemia (JMML) is a pediatric myeloproliferative neoplasm that be

99 Juvenile myelomonocytic leukemia (JMML) is a poor-prognosis childhood leukemia usually cau

100 Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive stem cell disease of earl

101 Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disorder.

102 Juvenile myelomonocytic leukemia (JMML) is a rare heterogeneous hematological malignancy o

103 Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative neoplasm of childhood

104 Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myeloid neoplasm characterized

105 Juvenile myelomonocytic leukemia (JMML) is a typically aggressive myeloid neoplasm of chil

106 Juvenile myelomonocytic leukemia (JMML) is a unique clonal hematopoietic disorder of early

107 Juvenile myelomonocytic leukemia (JMML) is a unique, aggressive hematopoietic disorder of

108 Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasia that

109 Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm in ch

110 Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of ch

111 Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of yo

112 Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric mixed myelodysplastic/m

113 Juvenile myelomonocytic leukemia (JMML) is an early childhood disease for which there is n

114 Juvenile myelomonocytic leukemia (JMML) is characterized by hypersensitivity to granulocyt

115 Juvenile myelomonocytic leukemia (JMML) is characterized by myelomonocytic cell overproduc

116 y, using a juvenile myelomonocytic leukemia (JMML) patient-specific assay we demonstrate the ability

117 even (71%) juvenile myelomonocytic leukemia (JMML) patients and from 12 of 20 (60%) adult chronic mye

118 (MDS) and juvenile myelomonocytic leukemia (JMML) treated in a uniform fashion on Children's Cancer

119 innings of juvenile myelomonocytic leukemia (JMML) with the generation of induced pluripotent stem ce

120 genesis of juvenile myelomonocytic leukemia (JMML), a fatal childhood disease, the PI3K-Akt signaling

121 lopment of juvenile myelomonocytic leukemia (JMML), a fatal myeloproliferative disease (MPD).

122 iated with juvenile myelomonocytic leukemia (JMML), a myeloproliferative disease (MPD) of early child

123 isposed to juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative neoplasm (MPN) t

124 S), 60 had juvenile myelomonocytic leukemia (JMML), and 6 infants with Down syndrome had a transient

125 genesis of juvenile myelomonocytic leukemia (JMML), demonstrating that mutant Shp2 induces granulocyt

126 (APL) and juvenile myelomonocytic leukemia (JMML), we evaluated UAB8 isomers in in vitro assays whic

127 ddition to juvenile myelomonocytic leukemia (JMML), which is a myeloproliferative disorder (MPD).

128 crisis and juvenile myelomonocytic leukemia (JMML).

129 ed risk of juvenile myelomonocytic leukemia (JMML).

130 nsyndromic juvenile myelomonocytic leukemia (JMML).

131 including juvenile myelomonocytic leukemia (JMML).

132 tivated in juvenile myelomonocytic leukemia (JMML).

133 isposed to juvenile myelomonocytic leukemia (JMML).

134 rticularly juvenile myelomonocytic leukemia (JMML).

135 including juvenile myelomonocytic leukemia (JMML).

136 variant of chronic myelomonocytic leukemia (JMML/MP-CMML).

137 In addition, this new fetal-like JMML subgroup presented with reduced levels of most memb

138 central role in establishing and maintaining JMML/MP-CMML phenotypes in human and mouse.

139 The data show that malignant JMML and lymphoma cells share a common loss of genetic m

140 ses a progressive MPN that accurately models JMML and chronic myelomonocytic leukemia (CMML).

141 etal liver cells from Nf1 mutant mice models JMML; however, this system has important limitations as

142 yeloproliferative disorder (MPD) that models JMML.

143 eractivation of GMR signaling in Cbl-mutated JMML cells.

144 e subtypes, PTPN11-, NRAS-, and KRAS-mutated JMML, are characterized by heterozygous somatic gain-of-

145 child with PTPN-11-, K-RAS-, or NF1-mutated JMML and to the majority of those with N-RAS mutations.

146 nce of NF1 mutations in approximately 30% of JMML cases.

147 standing the genomic and epigenomic basis of JMML will not only greatly improve precise decision maki

148 (HSPCs) are the disease propagating cells of JMML.

149 In vitro differentiation of JMML iPSCs produced myeloid cells with increased prolife

150 Successful engraftments of JMML primary samples were also achieved in all NSGS reci

151 A hallmark feature of JMML is acquired hypersensitivity by clonal myeloid prog

152 sm (MPN) that recapitulates many features of JMML and MP-CMML.

153 led to recapitulate the defining features of JMML due to in utero lethality, nonhematopoietic express

154 n addition, leukemic blasts in one-fourth of JMML patients present with monosomy 7, and more than hal

155 The molecular hallmark of JMML is hyperactivation of the Ras/MAPK pathway with the

156 NA sequencing reveal marked heterogeneity of JMML hematopoietic stem/progenitor cells (HSPCs), includ

157 assays reveal interpatient heterogeneity of JMML LSCs, which are present in, but not confined to, th

158 ributed to the selective hypersensitivity of JMML cells to granulocyte macrophage-colony-stimulating

159 with resultant selective hypersensitivity of JMML cells to granulocyte-macrophage colony-stimulating

160 intact cells, and that CTL immunotherapy of JMML could be directed against the gamma-globin-derived

161 nd demonstrated dose-dependent inhibition of JMML colony growth.

162 en made in defining the genomic landscape of JMML.

163 F of leukemic progenitors from a majority of JMML and CMML patients suggests that this agent could ha

164 N and mimics many clinical manifestations of JMML in terms of age of onset, aggressiveness, and organ

165 e have previously developed a mouse model of JMML through reconstitution of lethally irradiated mice

166 Here, we have developed a model of JMML using mice that express KrasG12D in multipotent pro

167 bly, in a patient derived xenograft model of JMML, leukemia-initiating stem and progenitor cells were

168 Utilizing an Shp2(E76K/+) murine model of JMML, we show that the combination of 5-Aza and PD-901 m

169 NF1 gene was involved in the pathogenesis of JMML in children without a clinical diagnosis of NF1.

170 The pathogenesis of JMML involves deregulated cytokine signal transduction t

171 le of hyperactive Ras in the pathogenesis of JMML.

172 tations in the initiation and progression of JMML and TLL/L remain elusive.

173 Consequently, a significant proportion of JMML patients without identifiable pathogenesis prompted

174 RNA sequencing of JMML LSC reveals up-regulation of stem cell and fetal ge

175 Studies of JMML are constrained by limited access to patient tissue

176 A subset of JMML patients harbor CBL mutations associated with 11q a

177 vide an innovative approach for treatment of JMML, with the potential for limiting toxicity resulting

178 explore the pathophysiology and treatment of JMML.

179 ains elusive how GM-CSF signaling impacts on JMML/MP-CMML initiation and progression.

180 closer to 22 healthy controls than to other JMML cases.

181 The leukemic progenitors from the two other JMML patients showed intermediate sensitivity to DT388-G

182 associated with poor clinical outcome in our JMML patient series but was not independent from other p

183 A second allograft is recommended if overt JMML relapse occurs after transplantation.

184 In most patients, JMML has a progressive course leading to death by virtue

185 TAT5/ERK phosphorylation, similar to primary JMML cells from patients.

186 The reduced JMML features in drug-treated mice were associated with

187 therapy in children with relapsed/refractory JMML.

188 rikingly, an anti-inflammatory agent rescued JMML-like MPN in Shp2(D61G) zebrafish embryos.

189 on and translation system was used to screen JMML marrows from 20 children for NF1 mutations that res

190 disomy that contains the CBL gene in several JMML samples, and subsequently identified CBL mutations

191 ted for their ability to inhibit spontaneous JMML granulocyte-macrophage colony growth.

192 nse was triggered in the HSPCs from sporadic JMML patients and syndromic NS zebrafish, which potentia

193 n nonsyndromic children, whereas 2 subtypes, JMML in neurofibromatosis type 1 and JMML in children wi

194 s in PTPN11 account for 34% of non-syndromic JMML.

195 e far less sensitive to these compounds than JMML hematopoietic progenitors.

196 These data support the hypothesis that JMML can arise in a pluripotent hematopoietic cell.

197 e only patient tested and this suggests that JMML may be the presenting feature of NF1 in some childr

198 ble activity to the natural retinoids in the JMML cell assays.

199 ied single nucleotide polymorphism arrays to JMML patients, somatic uniparental disomy 11q was detect

200 Current strategies for treating JMML include using the hypomethylating agent, 5-azacitid

201 em cells (iPSCs) from malignant cells of two JMML patients with somatic heterozygous p.E76K missense

202 se as a critical oncogenic driver underlying JMML.

203 RALD has an indolent clinical course whereas JMML is fatal if left untreated.

204 t common mutations in PTPN11 associated with JMML caused a gain of function.

205 Because 10% to 14% of children with JMML have a clinical diagnosis of NF1, these data are co

206 c/molecular remissions in some children with JMML, and its role in both reducing leukemia burden befo

207 what causes the early death in children with JMML, because transformation to acute leukemia is rare.

208 ular lesions in a cohort of 49 children with JMML, neurofibromatosis phenotype (and thereby NF1 mutat

209 Ninety children with JMML, various forms of MDS, or acute myeloid leukemia (A

210 primary leukemia cells from individuals with JMML.

211 ent stem cells (iPSCs) from individuals with JMML.

212 N11 mutations in 3 groups: (1) patients with JMML (n = 107); (2) patients with NS/MPD (n = 19); and (

213 characterized pooled cohort of patients with JMML (n = 128).

214 ecimens from 77 newly reported patients with JMML (n = 69) or NS/MPD (n = 8).

215 Other patients with JMML acquire activating RAS gene mutations.

216 al trials of MEK inhibitors in patients with JMML and CMML.

217 were detected in nearly 10% of patients with JMML and have been characterized as secondary events.

218 edict the survival outcomes of patients with JMML and high accuracy.

219 K/ERK and JAK/STAT in treating patients with JMML and MP-CMML.

220 Finally, we report two patients with JMML and PTPN11 mutations treated with 5-Aza, trametinib

221 Patients with JMML and refractory anemia (RA) or RA-excess blasts (RAE

222 ases); this was common both in patients with JMML and those with A-MDS.

223 e current standard of care for patients with JMML relies on allogeneic hematopoietic stem cell transp

224 Classifying patients with JMML using global DNA methylation profiles is useful for

225 the therapy of choice for most patients with JMML, curing more than 50% of affected children.

226 m of PTPN11 mutations found in patients with JMML, NS/MPD, and NS.

227 the cell surface of cells from patients with JMML.

228 tly identified in about 35% of patients with JMML; these mutations introduce amino acid substitutions