Investigating the mechanism of ITGA4/6-mediated chemoprotection of ALL cells

研究 ITGA4/6 介导的 ALL 细胞化学保护机制

基本信息

批准号：
8699167
负责人：
Yong-Mi Kim Kim
金额：
$ 32.86万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8699167
关键词：
ABL1 gene Acute Lymphocytic Leukemia Address Adhesions Adjuvant Adjuvant Therapy Adult Adult Acute Lymphocytic Leukemia Affect Antibodies Apoptotic B-Lymphocytes BCR/ABL1 Biological Assay Blocking Antibodies Bone Marrow Bone Marrow Cells Cell Adhesion Cell Adhesion Molecules Cells Chemoprotection Child Clinical Data Diagnosis Drug resistance Engraftment Environment FDA approved Frequencies Gene Expression Gene Expression Profiling Genetic Models Goals Hematopoietic Hematopoietic stem cells Homing In Vitro Integrins Knock-out Laminin Lead Ligands MAP Kinase Gene Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Mass Spectrum Analysis Mediating Modeling Molecular Outcome Pathway interactions Patient Care Patients Pharmaceutical Preparations Play Pre-B Acute Lymphoblastic Leukemia Proteomics Proto-Oncogene Proteins c-akt Recurrent disease Relapse Relative (related person)Residual Neoplasm Resistance Role Sampling Schedule Signal Transduction Site Toxic effect Tyrosine Kinase Inhibitor United States Vascular Cell Adhesion Molecule-1 Xenograft Model base chemotherapy cohort high risk in vivo leukemia loss of function mouse model natalizumab novel novel therapeutics public health relevance response self-renewal

ABL1 gene Acute Lymphocytic Leukemia Address Adhesions Adjuvant Adjuvant Therapy Adult Adult Acute Lymphocytic Leukemia Affect Antibodies Apoptotic B-Lymphocytes BCR/ABL1 Biological Assay Blocking Antibodies Bone Marrow Bone Marrow Cells Cell Adhesion Cell Adhesion Molecules Cells Chemoprotection Child Clinical Data Diagnosis Drug resistance Engraftment Environment FDA approved Frequencies Gene Expression Gene Expression Profiling Genetic Models Goals Hematopoietic Hematopoietic stem cells Homing In Vitro Integrins Knock-out Laminin Lead Ligands MAP Kinase Gene Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Mass Spectrum Analysis Mediating Modeling Molecular Outcome Pathway interactions Patient Care Patients Pharmaceutical Preparations Play Pre-B Acute Lymphoblastic Leukemia Proteomics Proto-Oncogene Proteins c-akt Recurrent disease Relapse Relative (related person)Residual Neoplasm Resistance Role Sampling Schedule Signal Transduction Site Toxic effect Tyrosine Kinase Inhibitor United States Vascular Cell Adhesion Molecule-1 Xenograft Model base chemotherapy cohort high risk in vivo leukemia loss of function mouse model natalizumab novel novel therapeutics public health relevance response self-renewal

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项目摘要

DESCRIPTION (provided by applicant): Acute lymphoblastic leukemia is the most common childhood cancer and the 10th most common adult cancer in the United States. Drug resistance remains a major problem in the treatment of acute lymphoblastic leukemia (ALL). The bone marrow (BM) environment, consisting of endosteal and perivascular niches, has been shown to promote cell adhesion-mediated drug resistance (CAM-DR) in leukemia cells. Incomplete response to chemotherapy results in persistence of resistant clones and minimal residual disease (MRD). The exact mechanisms for CAM-DR leading to MRD and approaches to address this problem remain elusive. Integrin ¿4 mediates adhesion of hematopoietic cells onto bone marrow cells and has been implicated in CAM- DR of leukemia cells. We have determined that integrins ¿4 and ¿6 are the most upregulated integrins in pre-B ALL. We hypothesize that ¿4 and ¿6 integrin-mediated adhesion of ALL cells to bone marrow stromal niches contributes to the persistence of MRD. Integrin ¿4 and ¿6 loss-of-function studies in a BCR-ABL1+ pre-B ALL mouse model resulted in loss of adhesion, increased chemo-sensitivity and decreased self-renewal capacity of ALL cells. Using FDA approved Natalizumab as ¿4 blocking antibody, we demonstrated in a xenogeneic ALL model that ¿4-blockade with chemotherapy can eradicate leukemia. Delineating the mechanistic basis for this concept will enable us to validate and further develop this treatment approach towards patient care.

描述（由适用提供）：急性淋巴细胞白血病是美国最常见的儿童癌症，也是美国第10个最常见的成年癌症。耐药性仍然是治疗急性淋巴细胞白血病（ALL）的主要问题。骨髓（BM）环境由内膜和血管周围壁ches组成，已被证明可促进白血病细胞中细胞粘合剂介导的耐药性（CAM-DR）。对化疗的不完全反应导致抗性克隆和最小残留疾病（MRD）的持续性。导致MRD的CAM-DR的确切机制和解决此问题的方法仍然难以捉摸。整联蛋白»4介导造血细胞在骨髓细胞上的粘附，并已在白血病细胞的CAMD中暗示。我们已经确定整联蛋白€4和€6是pre-b全部最上调的整联蛋白。我们假设€4和„ 6整联蛋白介导的所有细胞对骨髓基质壁ni的粘附有助于MRD的持续性。整联蛋白�4和„ 6在BCR-ABL1+-B中的功能丧失研究所有小鼠模型都导致粘合剂丧失，化学敏感性增加并提高了所有细胞的自我更新能力。使用FDA批准的Natalizumab作为4封闭抗体，我们在异构化中证明了所有模型，这些模型````with Atherotheration用化学疗法都可以放射性白血病。描述此概念的机械基础将使我们能够验证并进一步开发这种治疗方法来进行患者护理。