title: MiR-29a down-regulation in ALK-positive anaplastic large cell lymphomas contributes to apoptosis blockade through MCL-1 overexpression.
abstract: Although deregulated expression of specific microRNAs (miRNAs) has been described in solid cancers and leukemias, little evidence of miRNA deregulation has been reported in ALK-positive (ALK(+)) anaplastic large cell lymphomas (ALCL). These tumors overexpress the major antiapoptotic protein myeloid cell leukemia 1 (MCL-1), a situation that could compensate for the lack of BCL-2. We report that ALK(+) ALCL cell lines and biopsy specimens (n = 20) express a low level of miR-29a and that this down-modulation requires an active NPM-ALK kinase. Murine models (transgenic mice and mouse embryonic fibroblast [MEF] cells), which allow conditional NPM-ALK fusion protein expression, showed an increase of miR-29a expression in the absence of NPM-ALK. Concordant results were observed after the abolition of NPM-ALK kinase activity (siALK or PF-2341066) in NPM-ALK(+) ALCL cell lines. In addition, we showed that low expression of miR-29a, probably through methylation repression, plays an important regulatory role in MCL-1 overexpression that could promote tumor cell survival by inhibiting apoptosis. Enforced miR-29a expression was found to modulate apoptosis through inhibition of MCL-1 expression in ALCL cell lines and in a xenografted model, with a concomitant tumor growth reduction. Thus, synthetic miR-29a represents a potential new tool to affect tumorigenesis in these lymphomas.
authors.affiliation: Centre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, Université Paul Sabatier, , Toulouse Cedex 3, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Desjobert
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Renalier
authors.forename: Julie
authors.initials: J
authors.lastname: Bergalet
authors.forename: Emilie
authors.initials: E
authors.lastname: Dejean
authors.forename: Nicole
authors.initials: N
authors.lastname: Joseph
authors.forename: Anna
authors.initials: A
authors.lastname: Kruczynski
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Estelle
authors.initials: E
authors.lastname: Espinos
authors.forename: Fabienne
authors.initials: F
authors.lastname: Meggetto
authors.forename: Jérome
authors.initials: J
authors.lastname: Cavaillé
authors.forename: Georges
authors.initials: G
authors.lastname: Delsol
authors.forename: Laurence
authors.initials: L
authors.lastname: Lamant
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C532045:MIRN29a microRNA, human; C579094:Mcl1 protein, mouse; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases