Role of integrin alpha4 in drug resistant acute lymphoblastic leukemia.

摘要

Although cure rates for acute lymphoblastic leukemia (ALL) in children are high, relapse of ALL leads to death in 50-95%. Adult ALL patients have a survival rate of only 40%. Even survived, patients often suffer from late-term secondary toxic effects of current treatments. Therefore, chemotherapeutic drug resistance of ALL cells remains a major problem and less toxic and more efficient therapies are needed. More than 80% of first relapse of childhood and adult ALL occurs in the bone marrow. Interaction of normal hematopoietic stem cells with the bone marrow (BM) stromal cells has been shown to provide mechanical support and facilitate proliferation and differentiation. BM stromal cells also provide protection of ALL cells from chemotherapy, thus contributing to drug resistance due to the lack of efficacy of current therapies. The exact mechanisms for stroma-mediated chemoprotection and approaches to address this problem remain elusive. In chapter two of this thesis, we summarize how we established a xenograft model of primary ALL cells to evaluate novel therapies. In chapter three, we use this preclinical model of primary ALL and focus on integrin alpha 4 as a central adhesion molecule for stromal-mediated chemoprotection and drug resistance of ALL. Integrin α4 is known to mediate adhesion of normal and malignant B-cell precursors in BM stromal cells. However, the functional modulation of integrin α4 and its consequences for drug resistance in ALL remains to be examined. According to gene expression analyses, integrin α4 is overexpressed in ALL patients and inversely correlated with the survival outcome. Therefore, we tested whether interference with α4-mediated stromal adhesion might be a new ALL treatment strategy. For this purpose, two models of leukemia were used: one pharmacological using antibody, like Tysabri, and small molecule inhibitor, like TBC3486, to target α4 of primary pre-B ALL and later in chapter 4 a genetic model (conditional α4 ablation of BCR-ABL1-induced murine leukemia). Conditional deletion of α4 sensitized murine leukemia cell to chemotherapy, Nilotinib. Adhesion of primary pre-B ALL cells was α4-dependent and inhibiting α4 sensitized primary ALL cells towards chemotherapy, VDL. Combination of chemotherapy with Tysabri prolonged survival of NOD/SCID recipients of primary ALL suggesting adjuvant integrin α4 inhibition as a novel strategy for pre-B ALL. Taken together, our data demonstrate that integrin α4-blockade with adjuvant chemotherapy can eradicate chemotherapy-resistant leukemia.