miR-135b mediates NPM-ALK-driven oncogenicity and renders IL-17-producing immunophenotype to anaplastic large cell lymphoma

Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Japan.
Blood (Impact Factor: 10.45). 12/2011; 118(26):6881-92. DOI: 10.1182/blood-2011-05-354654
Source: PubMed


Many transformed lymphoma cells show immune-phenotypes resembling the corresponding normal lymphocytes; thus, they provide a guide for proper diagnosis and present promising routes to improve their pathophysiologic understanding and to identify novel therapeutic targets. However, the underlying molecular mechanism(s) of these aberrant immune-phenotypes is largely unknown. Here, we report that microRNA-135b (miR-135b) mediates nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-driven oncogenicity and empowers IL-17-producing immunophenotype in anaplastic large cell lymphoma (ALCL). NPM-ALK oncogene strongly promoted the expression of miR-135b and its host gene LEMD1 through activation of signal transducer and activator of transcription (STAT) 3. In turn, elevated miR-135b targeted FOXO1 in ALCL cells. miR-135b introduction also decreased chemosensitivity in Jurkat cells, suggesting its contribution to oncogenic activities of NPM-ALK. Interestingly, miR-135b suppressed T-helper (Th) 2 master regulators STAT6 and GATA3, and miR-135b blockade attenuated IL-17 production and paracrine inflammatory response by ALCL cells, indicating that miR-135b-mediated Th2 suppression may lead to the skewing to ALCL immunophenotype overlapping with Th17 cells. Furthermore, antisense-based miR-135b inhibition reduced tumor angiogenesis and growth in vivo, demonstrating significance of this "Th17 mimic" pathway as a therapeutic target. These results collectively illuminated unique contribution of oncogenic kinase-linked microRNA to tumorigenesis through modulation of tumor immune-phenotype and microenvironment.

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Available from: Takashi Yao
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    • "The ability of miR-135b to target multiple tumour suppressors indicates an indiscriminate ability to promote tumour progression and metastasis. Other researchers have found that miR-135b may also contribute to mediate NPM-ALKassociated oncogenicity in large-cell lymphomas [23]. A miR-135b antagomir (Antago-135), which is able to functionally suppress miR-135b, effectively reduced metastasis and tumour burden, which suggests the potential for the development of miR-135b antagonists for lung cancer therapy [12]. "
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    • "To analyze the effects of ASP3026 in vivo, we generated and utilized a systemic NPM-ALK+ ALCL model in SCID mice and monitored tumor development using a bioluminescence-based imaging system. Contrary to the widely utilized NPM-ALK+ ALCL xenograft models that exploit localized, subcutaneous tumor engrafts [34, 35], our approach is much more relevant to clinical settings where NPM-ALK+ ALCL patients typically present with widely disseminated disease. Uninterrupted oral administration of ASP3026 was associated with total eradication of established systemic lymphoma tumors with no evidence of relapse throughout the entire period of the study. "
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    ABSTRACT: NPM-ALK⁺ T-cell anaplastic large-cell lymphoma (ALCL) is an aggressive type of cancer. Standard treatment of NPM-ALK⁺ ALCL is CHOP polychemotherapy. Although patients initially respond favorably to CHOP, resistance, relapse, and death frequently occur. Recently, selective targeting of ALK has emerged as an alternative therapeutic strategy. ASP3026 is a second-generation ALK inhibitor that can overcome crizotinib resistance in non-small cell lung cancer, and is currently being evaluated in clinical trials of patients with ALK⁺ solid tumors. However, NPM-ALK⁺ ALCL patients are not included in these trials. We studied the effects of ASP3026 on NPM-ALK⁺ ALCL cell lines in vitro and on systemic lymphoma growth in vivo. ASP3026 decreased the viability, proliferation, and colony formation, as well as induced apoptotic cell death of NPM-ALK⁺ ALCL cells. In addition, ASP3026 significantly reduced the proliferation of 293T cells transfected with NPM-ALK mutants that are resistant to crizotinib and downregulated tyrosine phosphorylation of these mutants. Moreover, ASP3026 abrogated systemic NPM-ALK⁺ ALCL growth in mice. Importantly, the survival of ASP3026-treated mice was superior to that of control and CHOP-treated mice. Our data suggest that ASP3026 is an effective treatment for NPM-ALK⁺ ALCL, and support the enrollment of patients with this lymphoma in the ongoing clinical trials.
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    • "It has been described in several studies that miR-135b is abnormally expressed in some types of tumor and could contribute to tumorigenesis [21-28]. Importantly, miR-135b has also been reported to be involved in the regulation of osteogenic differentiation [15,29]. "
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