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

Abstract

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.

p66Shc deficiency in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape

“…Of note, p66Shc −/− mice spontaneously develop age-related autoimmunity, 5 a feature frequently associated with CLL. 1 Interestingly, p66Shc downregulation in CLL B cells induces the expression of the inhibitory molecule ILT3, 39 suggesting that compensatory mechanisms might be operational to restrain CLL cell responses.…”

Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL

“…Another immune inhibitory receptor, LILRB4, was reported as tumor-associated antigen that is highly expressed on monocytic AML cells [64,65]. It was also reported as a selective marker of neoplastic B cells and HSCs from CLL patients [66]. LILRB4 targeting, either by antibodies or by CAR-T cells, impeded AML development [56,57].…”

E3 ubiquitin ligases in B-cell malignancies

“…Deltex1 has also been shown to promote the expression of ILT3, the immunoglobulin-like transcript 3, in CLL. ILT3 is a receptor expressed by myeloid cells, which inhibits the activation of AKT following BCR-stimulation through the recruitment of active SHIP1 (Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1) 91 . Though ILT3 up-regulation is a marker of CLL cells, how Deltex1 synergistically acts with other specific CLL factors in the regulatory network remains to be understood.…”