Lymphopoietic niche editing by B-lineage leukemic cells and its implications for B cell progenitor and leukemic cell growth
Lymphopoietic niche editing by B-lineage leukemic cells and its implications for B cell progenitor and leukemic cell growth
批准号:
9807643
负责人:
JOAO PEREIRA
金额:
$25.13万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-06-25 至 2021-05-31
关键词:
Acute Lymphocytic LeukemiaAllogenicB-Cell Acute Lymphoblastic LeukemiaB-Cell DevelopmentB-LymphocytesBone MarrowCXCL12 geneCXCR4 geneCell AdhesionCell LineageCell ProliferationCellsChildhoodCodeDNA Double Strand BreakDefectDevelopmentDown-RegulationElderlyFaceGene Expression ProfilingGenesGeneticGlutamineGrantGrowthHematologic NeoplasmsHematopoieticHematopoietic NeoplasmsHumanImmune System DiseasesIn VitroInterleukin-7LaboratoriesLeukemic CellLigandsLightLoxP-flanked alleleLymphoidMeasuresMediatingMesenchymal Stem CellsMetabolismModelingMolecularMouse StrainsMovementMusMutationNorleucineNutrientPathway interactionsPatientsPhenocopyPhiladelphiaPhiladelphia ChromosomePhysiologicalPopulationProductionPublishingReagentReceptor SignalingReporterRewardsSamplingSourceStem cellsStromal CellsT-LymphocyteTestingTherapeuticTimeTumor Necrosis Factor-BetaWorkadaptive immunityartemisbasecell growthcell typechemotherapyefficacy testingexperimental studyfitnessglutamine analoghigh rewardhigh riskin vivoinhibitor/antagonistleukemialymphotoxin beta receptormouse modelneoantigensnovelnovel therapeutic interventionpatient populationpreventprogenitorreceptorrepair enzymesuccesssynergismtargeted treatmenttherapeutic evaluationtherapeutic targettreatment strategy
中文摘要
摘要:B细胞急性淋巴细胞性白血病(B-ALL)目前的化疗方案是
成功率较高。然而,化疗会导致长期的后遗症,特别是在儿科
人口。在老年人中,化疗往往不足以消除B-ALL,留下这些患者
没有其他治疗方法。因此,对新靶点和治疗策略的追求必须继续下去
面对特别敏感的患者群体的需求。B-ALL最流行的形式是
费城染色体PREB ALL。在过去的两年里,我们一直在研究
发育中的B淋巴细胞和骨髓中罕见但生理关键的基质细胞群
被称为间充质祖细胞(MPC),能产生白介素7(IL-7)。在最近发表的一项研究中
我们描述了在PROB和MPC之间以及在PREB细胞和MPC之间形成的两个单元电路
调节B细胞发育的早期。这些发现让我们有了一个意想不到的发现--
白血病Preb细胞和费城染色体Preb-ALL细胞与MPC物理上相互作用并关闭
骨髓间充质干细胞产生IL-7。在最近和未发表的研究中,我们鉴定了淋巴毒素
LTa1b2配体在白血病前期和白血病Preb细胞及淋巴毒素β受体(LTbR)的表达
在MPC上表达,作为控制MPC产生IL-7的分子机制。重要的是,转向-
停止非白血病B系细胞的发育会加速Preb-all的生长,这表明
这两种细胞类型都在争夺限制因素(S)。值得注意的是,我们的初步研究显示,Preb-All
细胞和非白血病B细胞祖细胞高度依赖细胞合成代谢营养物质谷氨酰胺
增殖/生长。结合我们未发表的发现,我们得出了这笔赠款的主要假设:1
靶向LTbR信号转导MPC改变骨髓微环境,降低PreB-B-R水平
所有细胞的生长;和2-Preb-ALL细胞与非白血病的“正常B细胞祖细胞”竞争限制
骨髓微环境中谷氨酰胺的含量。这些假说将在两个相关的
而是独立的目标。在目标1中,我们将测试LTbR信号在减缓骨髓MPC中的影响
抑制体内Preb-all的生长。我们将使用转基因小鼠模型和
LTbR阻断试剂以确定通过改变IL-7产生Preb-All是否在一定程度上抑制了生长
这允许T细胞在体内介导同种异体Preb-all的清除。在目标2中,我们将探索
谷氨酰胺拮抗剂谷氨酰胺类似物6-重氮-5-氧代-L去甲亮氨酸的治疗潜力
代谢,在体内阻止Preb-ALL细胞的增殖。这些目标的成功可能会产生重大影响
关于B-ALL的治疗,并为其他血癌的治疗开辟新的治疗策略。
英文摘要
Summary: B cell acute lymphoblastic leukemias (B-ALL) are currently treated with chemotherapy with a
relatively high success rate. However, chemotherapy causes long-lasting sequellae particularly in pediatric
populations. In the elderly, chemotherapy is often insufficient for eliminating B-ALL, leaving these patients
without therapeutic alternatives. Therefore, the pursuit for new targets and therapeutic strategies must go on to
face the needs of particularly sensitive populations of patients. The most prevalent form of B-ALL is the
Philadelphia chromosome preB ALL. Over the past 2 years we have been studying the crosstalk between
developing B lymphocytes and a rare but physiologically critical population of stromal cells in the bone marrow
known as mesenchymal progenitor cells (MPCs) that produce Interleukin-7 (IL-7). In a recently published study
we described two cell circuits formed between proB and MPCs, and between preB cells and MPCs, that
regulate early stages of B cell development. These findings led us to an unexpected discovery that pre-
leukemic preB cells and Philadelphia chromosome preB-ALL cells physically interact with MPCs and turn-off
IL-7 production by MPCs in bone marrow. In recent and unpublished studies we identified the lymphotoxin
LTa1b2 ligand expressed on pre-leukemic and leukemic preB cells and the lymphotoxin beta receptor (LTbR)
expressed on MPCs as the molecular mechanism that controls IL-7 production by MPCs. Importantly, turning-
off the development of non-leukemic B-lineage cells results in accelerated growth of preB-ALLs, suggesting
that both cell types compete for limiting factor(s). Remarkably, our preliminary studies revealed that preB-ALL
cells and non-leukemic B cell progenitors are highly dependent on the anabolic nutrient Glutamine for cell
proliferation/growth. Combined, our unpublished findings led us to the main hypotheses of this grant: 1- that
therapeutic targeting of LTbR signaling in MPCs alters the bone marrow microenvironment and reduces preB-
ALL cell growth; and 2- that preB-ALL cells compete with non-leukemic “normal B cell progenitors” for limiting
amounts of Glutamine in the bone marrow microenvironment. These hypotheses will be tested in two related
but independent aims. In aim 1, we will test the impact of LTbR signaling in bone marrow MPCs in slowing
down the growth of preB-ALLs in vivo. We will use a combination of genetically modified mouse models with
LTbR blocking reagents to determine if by altering IL-7 production preB-ALL growth is reduced to an extent
that allows for T cell-mediated clearance of allogeneic preB-ALLs in vivo. In Aim 2, we will explore the
therapeutic potential of the Glutamine analog 6-Diazo-5-oxo-L-norleucine, a potent antagonist of Glutamine
metabolism, in preventing preB-ALL cell proliferation in vivo. Success in these aims may have a major impact
on the treatment of B-ALL and open new therapeutic strategies for the treatment of other blood cancers.
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会议论文
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海外基金