HSC-Independent Mechanisms Underlying JMML
HSC-Independent Mechanisms Underlying JMML
批准号:
9178088
负责人:
REBECCA J. CHAN
金额:
$16.97万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-01 至 2018-06-30
关键词:
4 year oldAccountingAcuteAddressAdultAllogenicBiochemicalBiological AssayBlast PhaseBone MarrowCBL geneCell LineageCellsCharacteristicsChildChildhoodChronic Myeloid LeukemiaChronic PhaseClinicalCoupledCytomegalovirusDevelopmentDiseaseEmbryoEmbryonic DevelopmentEngraftmentExtramedullaryGranulocyte-Macrophage Colony-Stimulating FactorHematopoietic Stem Cell TransplantationHematopoietic stem cellsHemorrhageHomingHuman Herpesvirus 4HypersensitivityImmuneIndividualInfectionInflammationInflammatoryJuvenile Myelomonocytic LeukemiaKRAS2 geneKnock-inLaboratoriesMalignant - descriptorModalityMonitorMusMutationMyelogenousMyeloid CellsMyeloproliferative diseaseNF1 geneNatureOncogenesOncogenicOrgan failurePTPN11 genePatientsPeripheralProductionProtein Tyrosine PhosphataseProteinsPublishingReactive Oxygen SpeciesRegimenRelapseResidual stateResistanceRespiratory FailureSeriesSimplexvirusStem cell transplantSyndromeSystemTamoxifenTissuesTransplantationValidationVirus DiseasesYolk Saccancer cellchemotherapeutic agentchemotherapycytotoxicgain of functionimprovedin vivoinhibitor/antagonistinnovationleukemiamacrophagemortalitymouse modelneoplastic cellneutrophilpostnatalprogenitorrecombinase
中文摘要
项目总结/摘要
青少年粒单核细胞白血病(JMML)是最常见的骨髓增生性肿瘤(MPN),
儿童期,往往发生在4岁以下的幼儿中。JMML传统上
在一些实施方案中,所述抗体被表征为由于NF 1、CBL、KRAS、NRAS或PTPN 11中的突变而被Ras驱动。传统
细胞毒性化疗药物对JMML无效,唯一的治疗方式是同种异体
造血干细胞移植与其他MPN不同,JMML很少进展到爆炸危机;相反,
死亡是由于髓外肿瘤细胞扩张导致器官衰竭、呼吸衰竭、出血,或
感染值得注意的是,在异基因干细胞移植后,50%的儿童死于白血病复发。
JMML的复发率明显高于接受同种异体干细胞移植的个体。
移植用于慢性期的慢性粒细胞白血病(CML)(约7%的白血病复发),
暗示JMML发育的强造血干细胞(HSC)独立成分,
进展
我们设想了两种不同的机制,可能占一个HSC独立的手段JMML复发
异基因HSC移植后。首先,JMML起始的恶性细胞可在胚胎期出现,
在HSC之前和独立于HSC发展,并且在出生后作为自我补充的恶性肿瘤持续存在。
组织巨噬细胞或者,无论JMML细胞的来源如何,
JMML可能会破坏骨髓微环境,抑制正常供体细胞的扩增
移植后,允许残留的白血病细胞胜过正常移植物,并导致白血病
复发
为了解决这些可能性,我们将使用他莫昔芬诱导的Cre重组酶系统,这将允许
卵黄囊限制性表达的常见JMML突变,Shp 2D 61 Y,以确定是否卵黄囊限制性表达,
癌基因的表达足以促进MPN的出生后发育。此外,我们将检查抑制是否
促炎蛋白PI 3 K p110δ的表达,改善了归巢、植入、扩张和骨髓
WT供体细胞分化为患病的表达Shp 2D 61 Y的受体。
英文摘要
PROJECT SUMMARY/ABSTRACT
Juvenile myelomonocytic leukemia (JMML) is the most common myeloproliferative neoplasm (MPN) in
childhood, and tends to occur in very young children less than 4 years of age. JMML is traditionally
characterized as being Ras-driven due to mutations in NF1, CBL, KRAS, NRAS, or PTPN11. Traditional
cytotoxic chemotherapeutic agents are ineffective in JMML, and the only curative modality is allogeneic
hematopoietic stem cell transplantation. Unlike other MPNs, JMML rarely progresses to blast crisis; rather,
mortality is due to extramedullary tumor cell expansion leading to organ failure, respiratory failure, bleeding, or
infection. Notably, following allogeneic stem cell transplant, 50% of children succumb to leukemia relapse.
This relapse rate in JMML is substantially higher than that of individuals who receive allogeneic stem cell
transplant for chronic myelogenous leukemia (CML) in chronic phase (approximately 7% leukemia relapse),
implicating a strong hematopoietic stem cell (HSC)-independent component of JMML development and
progression.
We envision two distinct mechanisms that potentially account for a HSC-independent means of JMML relapse
after allogeneic HSC transplant. First, the JMML-initiating malignant cells may emerge during embryonic
development prior to and independently from HSCs, and persist postnatally as self-replenishing malignant
tissue macrophages. Alternatively, regardless of the origin of the JMML cells, the hyperinflammatory nature of
JMML may damage the bone marrow microenvironment, prohibiting the expansion of normal donor cells
following transplant, permitting residual leukemia cells to outcompete the normal graft, and leading to leukemia
relapse.
To address these possibilities, we will use the tamoxifen-inducible Cre recombinase system, which will permit
yolk sac-restricted expression of the common JMML mutation, Shp2D61Y, to determine if yolk sac-restricted
oncogene expression is sufficient for the post-natal development of MPN. Further, we will examine if inhibition
of the pro-inflammatory protein, PI3K p110δ, improves homing, engraftment, expansion, and myeloid
differentiation of WT donor cells into diseased, Shp2D61Y-expressing recipients.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Midwest Blood Club Symposium, 2012
-
批准号:8319059
-
项目类别:
-
资助金额:$0.5万
-
财政年份:2012
-
负责人:REBECCA J. CHAN
-
依托单位:
Role of Shp2 in FLT3-ITD-Induced Leukemogenesis
-
批准号:8634730
-
项目类别:
-
资助金额:$31.0万
-
财政年份:2011
-
负责人:REBECCA J. CHAN
-
依托单位:
Role of Shp2 in FLT3-ITD-Induced Leukemogenesis
-
批准号:8064517
-
项目类别:
-
资助金额:$31.96万
-
财政年份:2011
-
负责人:REBECCA J. CHAN
-
依托单位:
Role of Shp2 in FLT3-ITD-Induced Leukemogenesis
-
批准号:8444574
-
项目类别:
-
资助金额:$30.04万
-
财政年份:2011
-
负责人:REBECCA J. CHAN
-
依托单位:
Role of Shp2 in FLT3-ITD-Induced Leukemogenesis
-
批准号:8828104
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项目类别:
-
资助金额:$31.96万
-
财政年份:2011
-
负责人:REBECCA J. CHAN
-
依托单位:
Aberrant Monocytic Differentiation Induced by Gain-of-Function Shp2 Mutants
-
批准号:7903360
-
项目类别:
-
资助金额:$23.14万
-
财政年份:2009
-
负责人:REBECCA J. CHAN
-
依托单位:
Aberrant Monocytic Differentiation Induced by Gain-of-Function Shp2 Mutants
-
批准号:7731789
-
项目类别:
-
资助金额:$19.29万
-
财政年份:2009
-
负责人:REBECCA J. CHAN
-
依托单位:
International Symposium on Juvenile Myelomonocytic Leukemia (JMML)
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批准号:8986009
-
项目类别:
-
资助金额:$0.4万
-
财政年份:2007
-
负责人:REBECCA J. CHAN
-
依托单位:
International Symposium on Juvenile Myelomonocytic Leukemia (JMML)
-
批准号:8706070
-
项目类别:
-
资助金额:$0.5万
-
财政年份:2007
-
负责人:REBECCA J. CHAN
-
依托单位:
Activating PTPN11 and c-kit Mutations in Myeloproliferative Disorder
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批准号:7491071
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项目类别:
-
资助金额:$35.79万
-
财政年份:2005
-
负责人:REBECCA J. CHAN
-
依托单位:
Activating PTPN11 and c-kit Mutations in Myeloprolifera*
-
批准号:7120558
-
项目类别:
-
资助金额:$36.98万
-
财政年份:2005
-
负责人:REBECCA J. CHAN
-
依托单位:
Activating PTPN11 and c-kit Mutations in Myeloproliferative Disorder
-
批准号:7279271
-
项目类别:
-
资助金额:$35.91万
-
财政年份:2005
-
负责人:REBECCA J. CHAN
-
依托单位:
Activating PTPN11 and c-kit Mutations in Myeloprolifera*
-
批准号:7023407
-
项目类别:
-
资助金额:$37.88万
-
财政年份:2005
-
负责人:REBECCA J. CHAN
-
依托单位:
MOLECULAR MECHANISMS OF HEMATOPOIESIS AND LEUKEMIA
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批准号:6514337
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项目类别:
-
资助金额:$5.44万
-
财政年份:2002
-
负责人:REBECCA J. CHAN
-
依托单位:
MOLECULAR MECHANISMS OF HEMATOPOIESIS AND LEUKEMIA
-
批准号:6459514
-
项目类别:
-
资助金额:$4.73万
-
财政年份:2001
-
负责人:REBECCA J. CHAN
-
依托单位:
MOLECULAR MECHANISMS OF HEMATOPOIESIS AND LEUKEMIA
-
批准号:6062362
-
项目类别:
-
资助金额:$4.26万
-
财政年份:2000
-
负责人:REBECCA J. CHAN
-
依托单位:
BIOCHEMISTRY AND MOLECULAR BIOLOGY
-
批准号:2043132
-
项目类别:
-
资助金额:$2.19万
-
财政年份:1994
-
负责人:REBECCA J. CHAN
-
依托单位:
BIOCHEMISTRY AND MOLECULAR BIOLOGY
-
批准号:2043131
-
项目类别:
-
资助金额:$1.98万
-
财政年份:1993
-
负责人:REBECCA J. CHAN
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依托单位:
BIOCHEMISTRY AND MOLECULAR BIOLOGY
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批准号:3024070
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项目类别:
-
资助金额:$1.36万
-
财政年份:1992
-
负责人:REBECCA J. CHAN
-
依托单位:
海外基金