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

描述（由申请人提供）：急性淋巴细胞白血病是美国最常见的儿童癌症和第10位最常见的成人癌症。耐药仍然是急性淋巴细胞白血病（ALL）治疗中的一个主要问题。骨髓（BM）环境由内皮和血管周围壁龛组成，已被证明可促进白血病细胞粘附介导的耐药（CAM-DR）。对化疗的不完全反应导致耐药克隆的持续存在和微小残留病（MRD）。CAM-DR导致MRD的确切机制和解决这一问题的方法仍然难以捉摸。整合素4介导造血细胞与骨髓细胞的粘附，并与白血病细胞的CAM- DR有关。我们已经确定，在前b ALL中，整合蛋白4和6是表达上调最多的整合蛋白。我们假设整合素介导的ALL细胞与骨髓基质壁龛的粘附有助于MRD的持续存在。在BCR-ABL1+ pre-B ALL小鼠模型中，整合素4和整合素6功能丧失研究导致ALL细胞的粘附丧失、化学敏感性增加和自我更新能力下降。使用FDA批准的Natalizumab作为¿4阻断抗体，我们在异种ALL模型中证明了¿4阻断与化疗可以根除白血病。描述这一概念的机制基础将使我们能够验证和进一步发展这种治疗方法对患者的护理。

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.