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 remains a disease for which few curative therapies

6 JMML was characterized by young age at onset and promine

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

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

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

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

11 A JMML mouse model, achieved through homozygous deletion o

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

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

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

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

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

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

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

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

20 had no additional adverse effect on MDS and JMML.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

37 The optimum treatment for JMML remains unknown.

38 perhaps indicating a potential treatment for JMML.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

57 Outcomes in JMML vary markedly from spontaneous resolution to rapid

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

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

60 firmed the involvement of deregulated Ras in JMML pathogenesis.

61 76 was the most commonly affected residue in JMML (n = 45), with the Glu76Lys alteration (n = 29) bei

62 pendence in CMML, consistent with results in JMML.

63 icant inhibitory effects would still show in JMML cultures.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

108 ed risk of juvenile myelomonocytic leukemia (JMML).

109 nsyndromic juvenile myelomonocytic leukemia (JMML).

110 including juvenile myelomonocytic leukemia (JMML).

111 tivated in juvenile myelomonocytic leukemia (JMML).

112 isposed to juvenile myelomonocytic leukemia (JMML).

113 rticularly juvenile myelomonocytic leukemia (JMML).

114 including juvenile myelomonocytic leukemia (JMML).

115 crisis and juvenile myelomonocytic leukemia (JMML).

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

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

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

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

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

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

122 yeloproliferative disorder (MPD) that models JMML.

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

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

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

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

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

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

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

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

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

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

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

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

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

136 en made in defining the genomic landscape of JMML.

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

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

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

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

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

142 The pathogenesis of JMML involves deregulated cytokine signal transduction t

143 le of hyperactive Ras in the pathogenesis of JMML.

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

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

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

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

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

149 explore the pathophysiology and treatment of JMML.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

167 se as a critical oncogenic driver underlying JMML.

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

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

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

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

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

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

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

175 primary leukemia cells from individuals with JMML.

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

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

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

179 Other patients with JMML acquire activating RAS gene mutations.

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

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

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

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

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

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

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

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

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