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Ectopic ILT3 controls BCR-dependent activation of Akt in B-cell chronic lymphocytic leukemia

Vanessa Zurli, Giuliana Wimmer, Francesca Cattaneo, Veronica Candi, Emanuele Cencini, Alessandro Gozzetti, Donatella Raspadori, Giuseppe Campoccia, Francesca Sanseviero, Monica Bocchia, Cosima Tatiana Baldari and Anna Kabanova

Key points

  • ILT3 is ectopically expressed on mature CLL cells and CLL progenitors in the bone marrow.

  • ILT3 controls the activation of Akt kinase in CLL and contributes to a regulatory network defined by a SHIP-1/Deltex1 axis.

Abstract

The high proportion of long-term non-progressors among chronic lymphocytic leukemia (CLL) patients suggests the existence of a regulatory network which 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 which 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 stimulation. This effect was achieved through the dynamic coalescence of ILT3, B cell receptors 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.

  • Submitted March 29, 2017.
  • Accepted September 6, 2017.