Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy

Department of Pediatrics, Division of Hematology and Oncology, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, United States
Blood (Impact Factor: 10.45). 01/2013; 121(10). DOI: 10.1182/blood-2012-01-406272
Source: PubMed


The bone marrow (BM) provides chemoprotection for acute lymphoblastic leukemia (ALL) cells thus contributing to the lack of efficacy of current therapies. Integrin alpha4 (alpha4) mediates adhesion of normal and malignant B-cell precursors in BM, and, according to gene expression analyses from 207 children with high-risk pre-B ALL with minimal residual disease, is particularly highly expressed in patients with the poorest outcome. Therefore, we tested whether interference with alpha4-mediated stromal adhesion might be a new ALL treatment. For this purpose, two models of leukemia were used, one genetic (conditional alpha4 ablation of BCR-ABL1 (p210+)-induced murine leukemia) and one pharmacological (anti-functional alpha4 antibody treatment of primary pre-B ALL). Conditional deletion of alpha4 sensitized leukemia cell to Nilotinib. Adhesion of primary pre-B ALL cells was alpha4-dependent and alpha4 blockade sensitized primary ALL cells towards chemotherapy. Combination of chemotherapy with an anti-integrin alpha4 antibody, Natalizumab, prolonged survival of NOD/SCID recipients of primary ALL suggesting adjuvant integrin alpha4 inhibition as a novel strategy for pre-B ALL.

Download full-text


Available from: Hiroyuki Shimada, Sep 16, 2015
  • Source
    • "Similar results were obtained in lymphoblastic leukemia cells [106]. Here, targeting of ␣4 integrin sensitized the cells to different chemotherapeutics including Vincristin or Dexamethason [106]. Despite this promising preclinical data, the relevance of ␣4 integrin inhibitors for clinical therapy in particular for acute myeloid leukemia is still controversial. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Interlocking gene mutations, epigenetic alterations and microenvironmental features perpetuate tumor development, growth, infiltration and spread. Consequently, intrinsic and acquired therapy resistance arises and presents one of the major goals to solve in oncologic research today. Among the myriad of microenvironmental factors impacting on cancer cell resistance, cell adhesion to the extracellular matrix (ECM) has recently been identified as key determinant. Despite the differentiation between cell adhesion-mediated drug resistance (CAMDR) and cell adhesion-mediated radioresistance (CAMRR), the underlying mechanisms share great overlap in integrin and focal adhesion hub signaling and differ further downstream in the complexity of signaling networks between tumor entities. Intriguingly, cell adhesion to ECM is per se also essential for cancer cells similar to their normal counterparts. However, based on the overexpression of focal adhesion hub signaling receptors and proteins and a distinct addiction to particular integrin receptors, targeting of focal adhesion proteins has been shown to potently sensitize cancer cells to different treatment regimes including radiotherapy, chemotherapy and novel molecular therapeutics. In this review, we will give insight into the role of integrins in carcinogenesis, tumor progression and metastasis. Additionally, literature and data about the function of focal adhesion molecules including integrins, integrin-associated proteins and growth factor receptors in tumor cell resistance to radio- and chemotherapy will be elucidated and discussed.
    Seminars in Cancer Biology 08/2014; 31. DOI:10.1016/j.semcancer.2014.07.009 · 9.33 Impact Factor
  • Source
    • "If this was a general rule, then targeting the VLA-4-fibronectin interface would represent an even more leukemia cell specific target than VLA-4 proper. However, our own data show contributory roles of both ligands for chemoresistance of leukemia cells (and most strongly for VCAM1) at least in vitro (36), so that the situation currently remains unresolved. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chemotherapeutic drug resistance in acute lymphoblastic leukemia (ALL) is a significant problem, resulting in poor responsiveness to first-line treatment or relapse after transient remission. Classical anti-leukemic drugs are non-specific cell cycle poisons; some more modern drugs target oncogenic pathways in leukemia cells, although in ALL these do not play a very significant role. By contrast, the molecular interactions between microenvironment and leukemia cells are often neglected in the design of novel therapies against drug resistant leukemia. It was shown however, that chemotherapy resistance is promoted in part through cell-cell contact of leukemia cells with bone marrow (BM) stromal cells, also called cell adhesion-mediated drug resistance (CAM-DR). Incomplete response to chemotherapy results in persistence of resistant clones with or without detectable minimal residual disease (MRD). Approaches for how to address CAM-DR and MRD remain elusive. Specifically, studies using anti-functional antibodies and genetic models have identified integrin alpha4 as a critical molecule regulating BM homing and active retention of normal and leukemic cells. Pre-clinical evidence has been provided that interference with alpha4-mediated adhesion of ALL cells can sensitize them to chemotherapy and thus facilitate eradication of ALL cells in an MRD setting. To this end, Andreeff and colleagues recently provided evidence of stroma-induced and alpha4-mediated nuclear factor-κB signaling in leukemia cells, disruption of which depletes leukemia cells of strong survival signals. We here review the available evidence supporting the targeting of alpha4 as a novel strategy for treatment of drug resistant leukemia.
    Frontiers in Oncology 05/2014; 4:99. DOI:10.3389/fonc.2014.00099
  • Source
    • "For instance, the α4β1 integrin interaction with fibronectin prevents apoptosis in B cell chronic lymphocytic leukemia (22). Blocking integrin alpha4 can sensitize drug resistant of pre-B acute lymphoblastic leukemia to chemotherapy (23). The interaction between VLA-4 on acute myeloid leukemic cells and fibronectin on stromal cells is crucial in minimal residual disease and for acute myelogenous leukemia prognosis (24). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute lymphoblastic leukemia bearing the Philadelphia chromosome is among the most difficult types of ALL to cure. However, the advent of targeted tyrosine kinase inhibitor (TKI) imatinib has ushered in a new era of treatments that have the potential to be less toxic to patients. Integrins and tyrosine kinases play important roles in mediating and transducing signals for cell survival and suppressing apoptosis. Focal adhesion kinase (FAK) is a non-receptor type tyrosine kinase that is constitutively activated in Ph+ ALL. We sought to investigate the specificity of integrin α5β1 (VLA-5) on Ph+ leukemia by its expression and function. We found VLA-5 expression increases after serum starvation. Integrin α5 inhibitory antibody inhibited adhesion of Ph+ leukemia to human fibronectin and acted synergistically with imatinib to induce Ph+ leukemia cell apoptosis. We used different strategies to block integrin signaling and knocked down the expression of integrin VLA-5 to observe the effect on proliferation and engraftment of Ph+ leukemia cells in immunodeficient mice. We found that blocking integrin activity by incubating Ph+ leukemia cells with disintegrin, a peptide inhibitor of integrins, or α5 inhibitory antibody, or knocking down the α5 integrin subunit impaired and delayed the engraftment of Ph+ leukemia in immunodeficient mice. We then treated mice xenografted with Ph+ leukemia cells with the FAK inhibitor TAE226 in combination with a BCR-ABL TKI nilotinib. While 2 weeks of treatment with TAE226 alone did not significantly inhibit leukemia growth in mice, TAE226 in combination with nilotinib provided the most optimum growth inhibition at 4-6 weeks. We conclude that blocking VLA-5 signaling or combining FAK inhibitors with TKI targeting BCL/ABL might be good strategies to improve treatments in patients with Ph+ ALL. By altering Ph+ leukemia cell interactions with the microenvironment, we may increase their susceptibility to therapy targeting BCR/ABL.
    Frontiers in Oncology 05/2014; 4:112. DOI:10.3389/fonc.2014.00112
Show more