title: A novel, non-canonical splice variant of the Ikaros gene is aberrantly expressed in B-cell lymphoproliferative disorders.
abstract: The Ikaros gene encodes a Krüppel-like zinc-finger transcription factor involved in hematopoiesis regulation. Ikaros has been established as one of the most clinically relevant tumor suppressors in several hematological malignancies. In fact, expression of dominant negative Ikaros isoforms is associated with adult B-cell acute lymphoblastic leukemia, myelodysplastic syndrome, acute myeloid leukemia and adult and juvenile chronic myeloid leukemia. Here, we report the isolation of a novel, non-canonical Ikaros splice variant, called Ikaros 11 (Ik11). Ik11 is structurally related to known dominant negative Ikaros isoforms, due to the lack of a functional DNA-binding domain. Interestingly, Ik11 is the first Ikaros splice variant missing the transcriptional activation domain. Indeed, we demonstrated that Ik11 works as a dominant negative protein, being able to dimerize with Ikaros DNA-binding isoforms and inhibit their functions, at least in part by retaining them in the cytoplasm. Notably, we demonstrated that Ik11 is the first dominant negative Ikaros isoform to be aberrantly expressed in B-cell lymphoproliferative disorders, such as chronic lymphocytic leukemia. Aberrant expression of Ik11 interferes with both proliferation and apoptotic pathways, providing a mechanism for Ik11 involvement in tumor pathogenesis. Thus, Ik11 could represent a novel marker for B-cell lymphoproliferative disorders.
authors.affiliation: Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Capece
authors.forename: Francesca
authors.initials: F
authors.lastname: Zazzeroni
authors.forename: Maria Michela
authors.initials: MM
authors.lastname: Mancarelli
authors.forename: Daniela
authors.initials: D
authors.lastname: Verzella
authors.forename: Mariafausta
authors.initials: M
authors.lastname: Fischietti
authors.forename: Ambra
authors.initials: A
authors.lastname: Di Tommaso
authors.forename: Rita
authors.initials: R
authors.lastname: Maccarone
authors.forename: Sara
authors.initials: S
authors.lastname: Plebani
authors.forename: Mauro
authors.initials: M
authors.lastname: Di Ianni
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Edoardo
authors.initials: E
authors.lastname: Alesse
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation; D005091:Exons; D015870:Gene Expression; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006801:Humans; D051740:Ikaros Transcription Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000378:metabolism; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000235:genetics; D021381:Protein Transport; D059368:RNA Isoforms; D016415:Sequence Alignment
chemical_list: D059368:RNA Isoforms; D051740:Ikaros Transcription Factor