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

描述(申请人提供)：急性淋巴细胞性白血病是美国最常见的儿童癌症和第10种最常见的成人癌症。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，包括骨内和血管周围的微环境，已被证明促进了白血病细胞的细胞黏附介导的耐药(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黏附，并与白血病细胞的CAM-DR有关。我们已经确定整合素？4和？6是前B-ALL中上调最多的整合素。我们推测，整合素介导的所有细胞与骨髓基质壁龛的黏附有助于MRD的持久性。在BCR-ABL1+Pre-B ALL小鼠模型中进行的整合素？4和？6功能丧失研究导致所有细胞的黏附丧失、化疗敏感性增加和自我更新能力降低。用FDA批准的那他珠单抗作为阻断抗体，我们在异种ALL模型中证明了阻断联合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并进一步发展这种治疗方法用于患者护理。

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.