Although intrinsic apoptosis defects are causal to the extended survival of chronic lymphocytic leukemia (CLL) B cells, several lines of evidence support a contribution of the peripheral lymphoid organs and BM microenvironment to the extended lifespan of leukemic B cells. Lymphocyte trafficking is controlled by homing signals provided by stromal cellderived chemokines and egress signals provided by sphingosine-1-phosphate (S1P). In the present study, we show that expression of S1P1, the S1P receptor responsible for lymphocyte egress, is selectively reduced in CLL B cells with unmutated IGHV. Expression of S1P2, which controls B-cell homeostasis, is also impaired in CLL B cells but independently of the IGHV mutational status. We provide evidence herein that p66Shc, a Shc adaptor family member the deficiency of which is implicated in the apoptosis defects of CLL B cells, controls S1P1 expression through its pro-oxidant activity. p66Shc also controls the expression of the homing receptor CCR7, which opposes S1P1 by promoting lymphocyte retention in peripheral lymphoid organs. The results of the present study provide insights into the regulation of S1P1 expression in B cells and suggest that defective egress caused by impaired S1P1 expression contributes to the extended survival IntroductionAlthough progressive accumulation of monoclonal CD5 ϩ B cells in the blood, peripheral lymphoid organs, and BM is the hallmark of chronic lymphocytic leukemia (CLL), the clinical course of this disorder is highly variable, ranging from a stable disease that may only require monitoring over time to a progressive, severe disease. 1,2 Several markers have been associated with poor prognosis. Coupled to the cytogenetic abnormalities, the mutational status of immunoglobulin heavy chain variable region (IGHV) genes is the most valuable marker presently available, with unmutated IGHV found in patients who develop aggressive disease. 3 Nevertheless, the onset of disease progression and response to treatment are to date largely unpredictable.At variance with other hematologic malignancies, CLL B cells are usually arrested at G 0 /G 1 and their accumulation is the result of an abnormally prolonged survival rather than uncontrolled proliferation. 1,2 Intrinsic defects in the apoptotic machinery underlie the prolonged lifespan of CLL B cells, a major target being the Bcl-2 family, in which overexpression of antiapoptotic members (Bcl-2 and Mcl-1) or impaired expression of proapoptotic members (Bax and Bak) tilts the balance toward cell survival. 4 Extrinsic factors consisting mainly of stromal cell-derived chemokines (CXCL12, CXCL13, CCL19, and CCL21) also to contribute to the extended lifespan of CLL B cells by providing survival cues during their transit through peripheral lymphoid tissues and BM. 5 Lymphocyte trafficking is tightly controlled by the chemokines present in the lymphoid microenvironment and the chemokine receptors expressed by the lymphocyte itself. 6 CLL B cells express increased levels of CXCR4, CCR7, and CXCR5, which has...
Key Points• In T-LGLL, autologous LGLdepleted PBMCs release high levels of IL-6 contributing to the constitutive STAT3 activation in leukemic LGL. • LeukemicLGLs show SOCS3 down-modulation, which is responsible for lack of the negative feedback mechanism controlling STAT3 activation.The JAK/STAT pathway is altered in T-cell large granular lymphocytic leukemia. In all patients, leukemicLGLs display upregulation of phosphorylated STAT3 (P-STAT3) that activates expression of many antiapoptotic genes. To investigate the mechanisms maintaining STAT3 aberrantly phosphorylated using transcriptional protein and functional assays, we analyzed interleukin (IL)-6 and suppressor of cytokine signaling-3 (SOCS3), 2 key factors of the JAK/STAT pathway that induce and inhibit STAT3 activation, respectively. We showed that IL-6 was highly expressed and released by the patients' peripheral blood LGL-depleted population, accounting for a trans-signaling process. By neutralizing IL-6 or its specific receptor with specific antibodies, a significant reduction of P-STAT3 levels and, consequently, LGL survival was demonstrated. In addition, we found that SOCS3 was down-modulated in LGL and unresponsive to IL-6 stimulation. By treating neoplasticLGLs with a demethylating agent, IL-6-mediated SOCS3 expression was restored with consequent P-STAT3 and myeloid cell leukemia-1 down-modulation. Methylation in the SOCS3 promoter was not detectable, suggesting that an epigenetic inhibition mechanism occurs at a different site. Our data indicate that loss of the inhibitor SOCS3 cooperates with IL-6 to maintain JAK/STAT pathway activation, thus contributing to leukemic LGL survival, and suggest a role of demethylating agents in the treatment of this disorder. (Blood. 2013;121(19):3843-3854)
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.