Integrin alpha4 blockade sensitizes drug resistant pre-B acute lymphoblastic leukemia to chemotherapy.
ABSTRACT 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.
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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 · 9.14 Impact Factor
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ABSTRACT: Integrins are a large family of cell surface receptors that bind extracellular matrix proteins. The interaction of integrins with extracellular matrix activates a number of intracellular signaling pathways involved in cell proliferation, differentiation, motility, and other essential cell functions. Integrins are critically important to both health and disease. In this review, we first describe the structure, functions, and signaling characteristics of integrins. We then discuss the roles of integrins in cancer progression. Finally, we recapitulate the laboratory and clinical efforts of targeting integrins as effective means of cancer therapy and diagnosis. This comprehensive review could help scientists and clinicians gain a complete understanding of integrins. It could also contribute toward the development of new drugs, new methods of diagnostics, and new treatment of cancers to benefit the patients in clinical practice.Anti-Cancer Drugs 07/2014; 25(10). DOI:10.1097/CAD.0000000000000145 · 1.89 Impact Factor
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ABSTRACT: Background. Ikaros, the product of IKZF1, is a regulator of lymphoid development and polymorphisms in the gene have been associated with the acute lymphoblastic leukemia (ALL). Additionally, IKZF1 deletions and mutations identify high-risk biological subsets of childhood ALL [Georgopoulos et al. Cell 1995; 83(2):289-299; Mullighan et al. N Engl J Md 2009; 360(5):470-480]. Procedures. To discover the underlying pathways modulated by Ikaros we performed gene expression and gene ontology analysis in IKZF1 deleted primary B-ALL pediatric patient samples. To validate downstream targets we performed qPCR on individual patient samples. We also created IKZF1 knockdown B-ALL cell lines with over 50% reduction of Ikaros, mimicking haplosufficient Ikaros deletions, and again performed qPCR to investigate the downstream targets. Finally, to understand the association of Ikaros deletion with a poor prognosis we challenged our IKZF1 knockdown cell lines with chemotherapy and compared responses to IKZF1 wild-type controls. Results. We report a specific gene expression signature of 735 upregulated and 473 down-regulated genes in IKZF1 deleted primary BALL pediatric patient samples. Gene ontology studies revealed an upregulation of genes associated with cell adhesion, cytoskeletal regulation, and motility in IKZF deleted patient samples. Validated up-regulated target genes in IKZF1 deleted patient samples included CTNND1 and PVRL2 (P = 0.0003 and P = 0.001), and RAB3IP and SPIB (P = 0.005 and P = 0.032) were down-regulated. In further studies in IKZF1 knockdown cell lines, apoptosis assays showed no significant chemoresistance. Conclusion. IKZF1 knockdown alone does not impart intrinsic chemotherapy resistance suggesting that the association with a poor prognosis may be due to additional lesions, microenvironmental interactions with the bone marrow niche, or other factors. (C) 2014 Wiley Periodicals, Inc.Pediatric Blood & Cancer 10/2014; 61(10). DOI:10.1002/pbc.25119 · 2.56 Impact Factor