Ectopic ILT3 controls BCR-dependent activation of Akt in B-cell chronic lymphocytic leukemia
| Autor: | Alessandro Gozzetti, Francesca Sanseviero, Donatella Raspadori, Anna Kabanova, Monica Bocchia, Giuliana Wimmer, Veronica Candi, Vanessa Zurli, Giuseppe Campoccia, Francesca Cattaneo, Emanuele Cencini, Cosima T. Baldari |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Src Homology 2 Domain-Containing Transforming Protein 1 Chronic lymphocytic leukemia Ubiquitin-Protein Ligases Immunology Receptors Antigen B-Cell Receptors Cell Surface Biology Biochemistry Immunomodulation 03 medical and health sciences hemic and lymphatic diseases Cell Line Tumor medicine Biomarkers Tumor Humans Receptors Immunologic Protein kinase B PI3K/AKT/mTOR pathway Membrane Glycoproteins Gene Expression Regulation Leukemic Stem Cells breakpoint cluster region Cell Biology Hematology medicine.disease Leukemia Lymphocytic Chronic B-Cell Up-Regulation Enzyme Activation Haematopoiesis 030104 developmental biology Tumor progression Cancer research Ectopic expression Stem cell CLL / ILT3 / BCR / Akt Transcriptome Proto-Oncogene Proteins c-akt Signal Transduction |
| Popis: | The high proportion of long-term nonprogressors among chronic lymphocytic leukemia (CLL) patients suggests the existence of a regulatory network that restrains the proliferation of tumor B cells. The identification of molecular determinants composing such network is hence fundamental for our understanding of CLL pathogenesis. Based on our previous finding establishing a deficiency in the signaling adaptor p66Shc in CLL cells, we undertook to identify unique phenotypic traits caused by this defect. Here we show that a lack of p66Shc shapes the transcriptional profile of CLL cells and leads to an upregulation of the surface receptor ILT3, the immunoglobulin-like transcript 3 that is normally found on myeloid cells. The ectopic expression of ILT3 in CLL was a distinctive feature of neoplastic B cells and hematopoietic stem cells, thus identifying ILT3 as a selective marker of malignancy in CLL and the first example of phenotypic continuity between mature CLL cells and their progenitors in the bone marrow. ILT3 expression in CLL was found to be driven by Deltex1, a suppressor of antigen receptor signaling in lymphocytes. Triggering of ILT3 inhibited the activation of Akt kinase upon B-cell receptor (BCR) stimulation. This effect was achieved through the dynamic coalescence of ILT3, BCRs, and phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 into inhibitory clusters at the cell surface. Collectively, our findings identify ILT3 as a signature molecule of p66Shc deficiency in CLL and indicate that ILT3 may functionally contribute to a regulatory network controlling tumor progression by suppressing the Akt pathway. |
| Databáze: | OpenAIRE |
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