Identification of differential and functionally active miRNAs in both anaplastic lymphoma kinase (ALK)+ and ALK− anaplastic large-cell lymphoma

Aberrant anaplastic lymphoma kinase (ALK) expression is a defining feature of many human cancers and was identified first in anaplastic large-cell lymphoma (ALCL), an aggressive non-Hodgkin T-cell lymphoma. Since that time, many studies have set out to identify the mechanisms used by aberrant ALK toward tumorigenesis. We have identified a distinct profile of micro-RNAs (miRNAs) that characterize ALCL; furthermore, this profile distinguishes ALK+ from ALK− subtypes, and thus points toward potential mechanisms of tumorigenesis induced by aberrant ALK. Using a nucleophosmin-ALK transgenic mouse model as well as human primary ALCL tumor tissues and human ALCL-derived cell lines, we reveal a set of overlapping deregulated miRNAs that might be implicated in the development and progression of ALCL. Importantly, ALK+ and ALK− ALCL could be distinguished by a distinct profile of “oncomirs”: Five members of the miR-17–92 cluster were expressed more highly in ALK+ ALCL, whereas miR-155 was expressed more than 10-fold higher in ALK− ALCL. Moreover, miR-101 was down-regulated in all ALCL model systems, but its forced expression attenuated cell proliferation only in ALK+ and not in ALK− cell lines, perhaps suggesting different modes of ALK-dependent regulation of its target proteins. Furthermore, inhibition of mTOR, which is targeted by miR-101, led to reduced tumor growth in engrafted ALCL mouse models. In addition to future therapeutical and diagnostic applications, it will be of interest to study the physiological implications and prognostic value of the identified miRNA profiles.

[1]  R. Greil,et al.  microRNA-34a expression correlates with MDM2 SNP309 polymorphism and treatment-free survival in chronic lymphocytic leukemia. , 2010, Blood.

[2]  Enzo Medico,et al.  Gene expression profiling uncovers molecular classifiers for the recognition of anaplastic large-cell lymphoma within peripheral T-cell neoplasms. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  M Paulli,et al.  Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma , 2009, Leukemia.

[4]  W. Pao,et al.  EML4-ALK: honing in on a new target in non-small-cell lung cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  Li Li,et al.  Exon Array Profiling Detects EML4-ALK Fusion in Breast, Colorectal, and Non–Small Cell Lung Cancers , 2009, Molecular Cancer Research.

[6]  P. Szankasi,et al.  The proteomic signature of NPM/ALK reveals deregulation of multiple cellular pathways. , 2009, Blood.

[7]  Kathryn A. O’Donnell,et al.  Therapeutic microRNA Delivery Suppresses Tumorigenesis in a Murine Liver Cancer Model , 2009, Cell.

[8]  R. Speich,et al.  Interleukin-6 Modulates the Expression of the Bone Morphogenic Protein Receptor Type II Through a Novel STAT3–microRNA Cluster 17/92 Pathway , 2009, Circulation research.

[9]  Jian-Rong Yang,et al.  MicroRNA-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. , 2009, Cancer research.

[10]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[11]  S. Varambally,et al.  Genomic Loss of microRNA-101 Leads to Overexpression of Histone Methyltransferase EZH2 in Cancer , 2008, Science.

[12]  S. Ogawa,et al.  Oncogenic mutations of ALK kinase in neuroblastoma , 2008, Nature.

[13]  C. Croce,et al.  Human Cytomegalovirus Infection Alters the Expression of Cellular MicroRNA Species That Affect Its Replication , 2008, Journal of Virology.

[14]  J. Mendell.  miRiad Roles for the miR-17-92 Cluster in Development and Disease , 2008, Cell.

[15]  R. Gascoyne,et al.  Genomic profiling reveals different genetic aberrations in systemic ALK‐positive and ALK‐negative anaplastic large cell lymphomas , 2008, British journal of haematology.

[16]  N. Shinton.  WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues , 2007 .

[17]  L. Kenner,et al.  The oncoprotein NPM-ALK of anaplastic large-cell lymphoma induces JUNB transcription via ERK1/2 and JunB translation via mTOR signaling. , 2007, Blood.

[18]  K. Elenitoba-Johnson,et al.  NPM-ALK oncogenic kinase promotes cell-cycle progression through activation of JNK/cJun signaling in anaplastic large-cell lymphoma. , 2007, Blood.

[19]  P. Włodarski,et al.  Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway , 2007, Oncogene.

[20]  Anton J. Enright,et al.  Requirement of bic/microRNA-155 for Normal Immune Function , 2007, Science.

[21]  P. Gaulard,et al.  Gene-expression profiling of systemic anaplastic large-cell lymphoma reveals differences based on ALK status and two distinct morphologic ALK+ subtypes. , 2007, Blood.

[22]  D. Alexander,et al.  CD2 promoter regulated nucleophosmin-anaplastic lymphoma kinase in transgenic mice causes B lymphoid malignancy. , 2006, Anticancer research.

[23]  Ling Tian,et al.  Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. , 2006, Cancer research.

[24]  D. Levy,et al.  New and Old Functions of STAT3: A Pivitol Target for Individualized Treatment of Cancer , 2005, Cell cycle.

[25]  Kathryn A. O’Donnell,et al.  c-Myc-regulated microRNAs modulate E2F1 expression , 2005, Nature.

[26]  S. Lowe,et al.  A microRNA polycistron as a potential human oncogene , 2005, Nature.

[27]  D. Levy,et al.  Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target , 2005, Nature Medicine.

[28]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[29]  K. Maclennan,et al.  Vav-promoter regulated oncogenic fusion protein NPM-ALK in transgenic mice causes B-cell lymphomas with hyperactive Jun kinase , 2003, Oncogene.

[30]  G. Inghirami,et al.  NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors. , 2003, Blood.

[31]  J. Renauld,et al.  Overexpression of NPM–ALK induces different types of malignant lymphomas in IL-9 transgenic mice , 2003, Oncogene.

[32]  S. Perkins,et al.  The nucleophosmin-anaplastic lymphoma kinase fusion protein induces c-Myc expression in pediatric anaplastic large cell lymphomas. , 2002, The American journal of pathology.

[33]  T. McDonnell,et al.  Overexpression of Mcl-1 in anaplastic large cell lymphoma cell lines and tumors. , 2002, The American journal of pathology.

[34]  D. Levy,et al.  Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death , 2002, Oncogene.

[35]  F. Behm,et al.  Retrovirus-mediated gene transfer of NPM-ALK causes lymphoid malignancy in mice. , 1997, Blood.

[36]  M. Raffeld,et al.  The activated anaplastic lymphoma kinase increases cellular proliferation and oncogene up‐regulation in rat la fibroblasts , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[37]  D N Shapiro,et al.  Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. , 1994, Science.

[38]  R. Warnke,et al.  CD30‐positive large cell lymphomas (‘Ki‐1 lymphoma’) are associated with a chromosomal translocation involving 5q35 , 1990, British journal of haematology.

[39]  J. Huret,et al.  Malignant histiocytosis: a specific t(2;5)(p23;q35) translocation? Review of the literature. , 1988, Blood.

[40]  G. Bosma,et al.  Concentration of IgG1 and IgG2a allotypes in serum of nude and normal allotype-congenic mice. , 1980, Journal of immunology.

[41]  Peter A. Jones,et al.  The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2. , 2009, Cancer research.

[42]  Stefano Volinia,et al.  Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[43]  P. Sherrington,et al.  A Ki-1 (CD30)-positive human cell line (Karpas 299) established from a high-grade non-Hodgkin's lymphoma, showing a 2;5 translocation and rearrangement of the T-cell receptor beta-chain gene. , 1988, Blood.