Abstract
Chronic lymphoid leukemia (CLL) is characterized by the accumulation of functionally defective CD5-positive B lymphocytes. The clinical course of CLL is highly variable, ranging from a long-lasting indolent disease to an unpredictable and rapidly progressing leukemia requiring treatment. It is thus important to identify novel factors that reflect disease progression or contribute to its assessment. Here, we report on a novel STAT3-mediated pathway that characterizes CLL B cells-extended viability and oxidative stress control. We observed that leukemic but not normal B cells from CLL patients exhibit constitutive activation of an atypical form of the STAT3 signaling factor, phosphorylated on serine 727 (Ser727) in the absence of detectable canonical tyrosine 705 (Tyr705)-dependent activation in vivo. The Ser727-phosphorylated STAT3 molecule (pSTAT3Ser727) is localized to the mitochondria and associates with complex I of the respiratory chain. This pSer727 modification is further controlled by glutathione-dependent antioxidant pathway(s) that mediate stromal protection of the leukemic B cells and regulate their viability. Importantly, pSTAT3Ser727, but neither Tyr705-phosphorylated STAT3 nor total STAT3, levels correlate with prolonged in vivo CLL B cells survival. Furthermore, STAT3 activity contributes to the resistance to apoptosis of CLL, but not normal B cells, in vitro. These data reveal that mitochondrial (Mt) pSTAT3Ser727 overactivity is part of the antioxidant defense pathway of CLL B cells that regulates their viability. Mt pSTAT3Ser727 appears to be a newly identified cell-protective signal involved in CLL cells survival. Targeting pSTAT3Ser727 could be a promising new therapeutic approach.
Highlights
Chronic lymphoid leukemia (CLL) B lymphoid cells (CLL-BCs) have a prolonged survival time in vivo but exhibit a high level of spontaneous apoptosis in vitro, highlighting the critical role of CLL B lymphoid cells (CLL-BC) microenvironment in this pathology.[1,2,3] Several stromal factors have been shown to be implicated in promoting CLLBC viability in vitro,[4,5,6] yet the exact mechanisms by which the microenvironment protects CLL cells from apoptosis in vivo remain unclear
We demonstrate that circulating CLL-BCs but not normal B lymphoid cells (N-BCs) overexpress an atypical mitochondria-associated pSTAT3Ser[727] moiety, the level of which correlates with prolonged CLL-BC survival in vivo
Statistical analyses confirmed that circulating CLL-BC expressed higher levels of pSTAT3Ser[727] as compared with N-BC (Figure 1c)
Summary
Overactivation of pSTAT3Ser[727] correlates with CLL-BC resistance to apoptosis. Circulating B cells were purified from healthy donors (n = 8) and CLL patients (Supplementary Table 1). Stromal support of CLL-BC can be reproduced when they are co-cultured with bone marrow stromal cell lines.[6,17] murine MS5 and human HS5 cells significantly reduce the level of CLL-BC spontaneous apoptosis, as assessed by Annexin V labeling and MTP probing (Figures 5a and b and Supplementary Figure 3) It maintains a strong level of pSTAT3Ser[727] immunolabeling in absence of any immunoreactive pSTAT3Tyr[705] in CLL-BC even after prolonged periods (Figures 5c and d, right panels, and Supplementary Figure 3), while the expression pS3-Ser[727] mt number / section total S3. A pronounced difference was observed in stroma co-cultured N-BC in which pSTAT3Ser[727] was distributed to the cytoplasmic and nuclear compartments, and not predominantly associated to mitochondria These observations indicate that stromal cells mimic in vitro the interactions between CLL-BC and their microenvironment that occur in vivo, in terms of CLL-BC protection from apoptosis, STAT3 phosphorylation status and intracellular localization. These data indicate that STAT3, but not STAT5, selectively supports CLL-BC survival in the absence of canonical pSTAT3Tyr[705] activation
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