SHIP‐1 protein level and phosphorylation status differs between CLL cells segregated by ZAP‐70 expression

Gabelloni, María Laura; Borge, Mercedes; Galletti, Jeremías Gastón; Cañones, Cristian; Calotti, Paula Fernández; Bezares, Raimundo F.; Avalos, Julio Sanchez; Giordano, Mirta; Gamberale, Romina

doi:10.1111/j.1365-2141.2007.06891.x

Cited by 15 publications

(15 citation statements)

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“…24,34,35 Expression and phosphorylation of SHIP1, an important mediator of anergy-associated signaling, is also mainly observed in ZAP70-negative CLL. 58 Taken together, these studies reveal variable levels of a constellation of anergic features in CLL. Importantly, where tested, these features are associated with relatively good prognosis, underlining the association between more pronounced anergy and favorable outcome.…”

Section: Variable Levels Of Anergy In U-cll and M-cllmentioning

confidence: 86%

The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergy

et al. 2014

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Biologists and clinicians agree that the B-cell receptor influences the behavior of chronic lymphocytic leukemia, and promising new drugs are aimed at receptor-associated kinases. Engagement of surface immunoglobulin by antigen is a key driver of malignant cells with outcome influenced by the nature of the cell, the level of stimulation and the microenvironment. Analysis of surface immunoglobulin-mediated signaling in the two major disease subsets defined by IGHV mutational status reveals bifurcation of responses toward proliferation or anergy. Mutated chronic lymphocytic leukemia, generally of relatively good prognosis, is mainly, but not exclusively, driven towards anergy in vivo. In contrast, unmutated chronic lymphocytic leukemia shows less evidence for anergy in vivo retaining more responsiveness to surface immunoglobulin M-mediated signaling, possibly explaining increased tumor progression. Expression and function of surface immunoglobulin M in unmutated chronic lymphocytic leukemia appear rather homogeneous, but mutated chronic lymphocytic leukemia exhibits a highly heterogeneous profile that may relate to further variable clinical behavior within this subset. Anergy should increase susceptibility to apoptosis but, in leukemic cells, this may be countered by overexpression of the B-cell lymphoma-2 survival protein. Maintained anergy spreads to chemokines and adhesion molecules, restraining homing and migration. However, anergy is not necessarily completely benign, being able to reverse and regenerate surface immunoglobulin M-mediated responses. A two-pronged attack on proliferative and anti-apoptotic pathways may succeed. Increased understanding of how chronic lymphocytic leukemia cells are driven to anergy or proliferation should reveal predictive biomarkers of progression and of likely response to kinase inhibitors, which could assist therapeutic decisions. ABSTRACT

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Section: Variable Levels Of Anergy In U-cll and M-cllmentioning

confidence: 86%

The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergy

et al. 2014

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Section: Discussionmentioning

confidence: 99%

“…29 Furthermore, increased SHIP-1 protein levels were reported in ZAP-70 Ϫ CLL cells, and it was found to be constitutively tyrosine phosphorylated to a greater extent than in ZAP-70 ϩ CLL cells. 30 Thus, increased SHIP-1 levels in ZAP-70 Ϫ CLL cells could be responsible for the short or absent CXCL12-induced ERK activation.In any case, the relative sensitivity of ZAP-70 ϩ CLL cells to CXCL12 compared with CLL cells lacking ZAP-70 appears rooted in the differential CXCL12-induced activation of the RAF/MEK/ ERK signaling pathway, making this pathway an attractive target for development of new treatments for patients with CLL, particularly those with ZAP-70 ϩ CLL who have a tendency for relatively rapid disease progression and shorter survival. To this end, we found that sorafenib blocked CXCL12-induced activation of the RAF/MEK/ERK pathway and sorafenib induced more pronounced apoptosis in ZAP-70 ϩ CLL than in ZAP-70 Ϫ CLL cells, suggesting an increased dependence on CLL cells from patients with ZAP-70 ϩ on this pathway for survival.…”

mentioning

confidence: 99%

Chronic lymphocytic leukemia cells receive RAF-dependent survival signals in response to CXCL12 that are sensitive to inhibition by sorafenib

Messmer¹,

Fecteau²,

O’Hayre

et al. 2011

Blood

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The chemokine CXCL12, via its receptor CXCR4, promotes increased survival of chronic lymphocytic leukemia (CLL) B cells that express high levels of -chainassociated protein (ZAP-70), a receptor tyrosine kinase associated with aggressive disease. In this study, we investigated the underlying molecular mechanisms governing this effect. Although significant differences in the expression or turnover of CXCR4 were not observed between ZAP-70 ؉ and ZAP-70 ؊ cell samples, CXCL12 induced greater intracellular Ca 2؉ IntroductionChronic lymphocytic leukemia (CLL) is a disease characterized by the accumulation of mature monoclonal B cells in the blood, secondary lymphoid tissue, and marrow. 1,2 Regardless of their apparent longevity in vivo, CLL B cells undergo apoptosis in vitro unless rescued by monocyte-derived nurse-like cells (NLCs) or marrow stromal cells. [3][4][5][6] In line with this hypothesis, the marrow is invariably infiltrated with CLL cells in patients, and the extent of infiltration correlates with clinical stage and prognosis. 5,7 These accessory cells also protect CLL cells from drug-induced apoptosis in vitro. 8 Thus, it has been postulated that CLL cells receive survival signals from these accessory cells, which constitute part of the CLL B-cell microenvironment in secondary lymphoid tissue and marrow. 6 Such niches could protect leukemia cells from spontaneous or drug-induced apoptosis in vivo, motivating the current study to better understand the survival pathways triggered by the microenvironment.Accessory cells such as NLCs protect CLL cells from apoptosis in vitro in part through the secretion of the stromal cell-derived factor-1␣ (renamed as CXCL12). 9,10 CXCL12 is a highly conserved chemokine that signals through the chemokine receptor CXCR4, which is expressed at high levels by CLL cells. 3,10,11 Although most noted for its role in directing cell migration, CXCL12 also provides survival stimuli to CLL cells and partially protects them from spontaneous or drug-induced apoptosis or both in vitro. 3,9 Further, the enhanced viability of these cells in the presence of CXCL12 can be blocked by antibodies to CXCL12 3 or peptide inhibitors of CXCR4. 8 In prior studies, it was found that treatment of CLL cells with CXCL12 induced activation of extracellular signal-regulated kinase (ERK). 8,12 In this study, we further examined the survival and signaling responses of CLL cells to CXCL12 to characterize the mechanism for the survival benefit. In addition, we compared the CXCL12-induced responses of CLL cells from 2 subgroups of patients, with high or low expression levels of -chain-associated protein of 70 kDa (ZAP-70), a tyrosine kinase whose high-level expression is correlated with increased risk of early disease progression and relatively short survival 12,13 . Methods Preparation of CXCL12CXCL12 was prepared as previously described. 14 Briefly, CXCL12 was expressed as a His-tag fusion protein and purified from inclusion bodies in BL21 Escherichia coli. Bacterial pellets were resuspended in 10mM Tris...

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“…Lyn-mediated SHP-1 recruitment to CD5 in B-CLL E Tibaldi et al previously observed, 33 though differently distributed. In fact, in normal B cells, SHP-1 remained almost exclusively confined to the cytosol, whereas in B-CLL cells, it was found equally partitioned between II-P and cytosol.…”

Section: Recruitment Of Shp-1 To the Plasma Membrane Is Mediated By Tmentioning

confidence: 99%

Lyn-mediated SHP-1 recruitment to CD5 contributes to resistance to apoptosis of B-cell chronic lymphocytic leukemia cells

et al. 2011

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In B-cell chronic lymphocytic leukemia (B-CLL) cells, Lyn, a tyrosine kinase belonging to the Src family, is overexpressed and atypically localized in an aberrant cytosolic complex in an active conformation, contributing to the unbalance between cell survival and pro-apoptotic signals. In this study, we demonstrate that Lyn constitutively phosphorylates the immunoreceptor tyrosine inhibitory motifs of the inhibitory cell surface co-receptor CD5, a marker of B-CLL. As a result, CD5 provides an anchoring site to Src homology 2 domain-containing phosphatase 1 (SHP-1), a known negative regulator of hematopoietic cell function, thereby triggering the negative B-cell receptor (BCR) signaling. The subsequent segregation of SHP-1 into two pools, one bound to the inhibitory co-receptor CD5 in an active form, the other in the cytosol in an inhibited conformation, proves crucial for withstanding apoptosis, as shown by the use of phosphotyrosine phosphatase-I-I, a direct inhibitor of SHP-1, or SHP-1 knockdown. These results confirm that Lyn exhibits the unique ability to negatively regulate BCR signaling, in addition to positively regulating effectors downstream of the BCR, and identify SHP-1 as a novel player in the deranged signaling network and as a potential attractive target for new therapeutic strategies in B-CLL.

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SHIP‐1 protein level and phosphorylation status differs between CLL cells segregated by ZAP‐70 expression

Cited by 15 publications

References 5 publications

The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergy

The outcome of B-cell receptor signaling in chronic lymphocytic leukemia: proliferation or anergy

Chronic lymphocytic leukemia cells receive RAF-dependent survival signals in response to CXCL12 that are sensitive to inhibition by sorafenib

Lyn-mediated SHP-1 recruitment to CD5 contributes to resistance to apoptosis of B-cell chronic lymphocytic leukemia cells

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