A Novel, Non-canonical Splice Variant of the Ikaros Gene Is Aberrantly Expressed in B-cell Lymphoproliferative Disorders

PLoS One

Maria Michela Mancarelli¹  Mariafausta Fischietti¹  Edoardo Alesse¹  Francesca Zazzeroni¹  Daniela Verzella¹  Rita Maccarone¹  Daria Capece¹  Sara Plebani²  Mauro Di Ianni²  Ambra Di Tommaso²  Alberto Gulino³ 

[1] Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy;Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy;Department of Molecular Medicine, “Sapienza” University of Rome, Rome, Italy

关键词: Apoptosis;    B cells;    Lymphomas;    Polymerase chain reaction;    Cell proliferation;    Myelodysplastic syndromes;    Hyperexpression techniques;    Acute lymphoblastic leukemia;   

DOI  :  10.1371/journal.pone.0068080

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY