The chemokine receptor CXCR4 has been implicated in the migration and trafficking of malignant B cells in several haematological malignancies. Over‐expression of CXCR4 has been identified in haematological tumours, but data concerning the role of this receptor in diffuse large B cell lymphoma (DLBCL) are lacking. CXCR4 is a marker of poor prognosis in various neoplasms, correlating with metastatic disease and decreased survival of patients. We studied CXCR4 involvement in cell migration in vitro and dissemination in vivo. We also evaluated the prognostic significance of CXCR4 in 94 biopsies of DLBCL patients. We observed that the level of expression of CXCR4 in DLBCL cell lines correlated positively with in vitro migration. Expression of the receptor was also associated with increased engraftment and dissemination, and decreased survival time in NOD/SCID mice. Furthermore, administration of a specific CXCR4 antagonist, AMD3100, decreased dissemination of DLBCL cells in a xenograft mouse model. In addition, we found that CXCR4 expression is an independent prognostic factor for shorter overall survival and progression‐free survival in DLBCL patients. These results show that CXCR4 mediates dissemination of DLBCL cells and define for the first time its value as an independent prognostic marker in DLBCL patients. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
True histiocytic lymphoma is considered a rare entity, and its diagnosis requires the concordance of morphological, immunophenotypic, and molecular findings. The association of malignant lymphoma with tumors in the monocyte-macrophage system has rarely been described. We present a case of mucosa-associated lymphoid tissue (MALT)-type low-grade B-cell lymphoma of the stomach, contiguous to a large tumoral mass that fulfills the morphological criteria (large cells with abundant pale cytoplasm and lobulated or kidney-shaped nuclei) and immunophenotypical features (human leukocyte antigen-DR locus, CD68, S-100, lysozyme immunoreactivity, and negative B- and T-cell markers) required for the diagnosis of histiocytic lymphoma. The patient remains in complete remission 18 months after surgery. The association of low grade-malignant lymphoma with tumors of monocyte-macrophage system cells is an exceedingly rare phenomenon. Whether these tumors are directly related or occur due to pure chance requires the identification of new cases and further study.
patients with CLL. BCMA expression was significantly higher on CLL cells than on normal B cells. BCR and CD40+IL4R stimulation promoted an increase in TACI and BCMA expression, cell viability and activation in normal B cells. A similar effect was observed in CLL cells after CD40+IL4R but not BCR stimulation. BCMA expression correlated with unmutated IGHV genes, poor-risk cytogenetics, and short progression-free survival. These findings further characterize the link between CD40+IL4R regulatory signals, BAFF, APRIL and their receptors and the survival of leukaemic cells and clinical features of CLL.
Focal adhesion (FA) proteins have been associated with transformation, migration, metastasis, and poor outcome in many neoplasias. We previously showed that these proteins were inhibited by E7123, a new celecoxib derivative with antitumor activity, in acute myeloid leukemia. However, little is known about FAs in diffuse large B cell lymphoma (DLBCL). This paper aimed to determine whether E7123 was effective against DLBCL and whether FAs were involved in its action.We evaluated the cytotoxicity and mechanism of action of E7123 and celecoxib in DLBCL cell lines. We also assessed the E7123 in vivo activity in a DLBCL xenograft model and studied FA signaling in primary DLBCL patient samples. We found that E7123 showed higher antitumor effect than celecoxib against DLBCL cells. Its mechanism of action involved deregulation of FA, AKT, and Mcl-1 proteins, a pathway that is activated in some patient samples, apoptosis-inducing factor release and induction of caspase-independent cell death. Moreover, E7123 showed suppression of in vivo tumor growth. These findings indicate that E7123 is effective against DLBCL in vitro and in vivo, with a mechanism of action that differs from that of most current therapies for this malignancy. IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most frequent non-Hodgkin lymphoma subtype. Cure rates have increased in recent years with the addition of rituximab to the combination chemotherapy: cyclophosphamide, doxorubicin, vincristine, and prednisone. 1 However, a significant percentage of patients still relapse because lymphoma cells acquire resistance to therapy, which is associated with defective caspase-dependent apoptotic pathways. [2][3][4] Paradoxically, almost all cytotoxic drugs currently in clinical use for DLBCL induce caspase-dependent apoptosis. 5 Thus, the development of novel compounds with mechanisms of action able to induce caspase-independent cell death probably improves the therapeutic outcome in DLBCL, particularly in patients who relapse after front-line therapy.Focal adhesion (FA) complexes are structures that link the actin filaments of the cytoskeleton with the extracellular matrix. They are formed by transmembrane receptors (integrins) that activate various protein kinases, including the focal adhesion kinase (FAK) and Src family kinases. 6 Crk-associated substrate (CAS) family proteins act as docking proteins that associate with FAK and Src to generate specific cellular responses. 7 FA proteins have been related to transformation, 8 migration, 9 metastasis, 10 and poor outcome 11 in many solid tumors and in some hematologic malignancies. 12,13 However, there are limited data regarding the role of FA proteins in DLBCL. To our knowledge, only FAK and the Src-family protein LYN have been studied in DLBCL. FAK is expressed in 70% of DLBCLs 14 and LYN is constitutively phosphorylated and required for DLBCL growth, survival, and proliferation. 15,16 Other FA proteins, such as HEF1 or p130Cas from the CAS family, or PYK2 from the FAK family, play crucial roles ...
Background The diagnosis of CLL is supported by a typical morphology and immunophenotype and usually does not present difficulties. Nevertheless, some patients with CLL can show an atypical phenotype, this raising the possibility of a lymphoproliferative disorder other than CLL. It has been recently shown that the expression of CD200 could be a rather consistent marker for CLL. Methods The expression of CD200 was investigated in 120 consecutive patients with B‐cell chronic lymphoproliferative disorders (B‐CLPD) (65 cases diagnosed as typical CLL, 16 atypical CLL, and 39 non‐CLL before entering the study) by using multiparametric flow cytometry with four color combinations. CD200 was analyzed as percentage of positive cells (≥30%) and MFIR expression. ROC curves were used to determine the cut‐off for the CD200 MFIR. Matutes score (MS) was used as comparator. Results All 81 (100%) patients classified as CLL and 25 of 39 (64.1%) classified as non‐CLL expressed high CD200 expression (≥30%). CD200 expression showed a high sensitivity (100%) and a low specificity (35.9%), and the accuracy was similar to that of Matutes score markers (range: 79.2%–86.7%); except SmIg that was 59.1%. The addition of CD200 to the Matutes score correctly identified 74 of 81 (91.4%) CLL cases including 9 of 16 atypical CLL cases. As per non CLL cases, 37 of 39 (94.9%) were correctly diagnosed by the modified system. Altogether, CD200 improved the diagnostic accuracy of Matutes score from 86.7% to 92.5% (P < .01). Conclusion These results show that CD200 is a valuable, albeit not specific, CLL diagnostic marker. © 2018 International Clinical Cytometry Society
Most acute myeloid leukemias (AMLs), including those with c-Kit or FLT3 mutations, show enhanced anchorage independent growth associated with constitutive activation of focal adhesion proteins. Moreover, these alterations increase cell survival, inhibit apoptosis and are associated with poor prognosis and resistance to chemotherapy. Therefore, the induction of apoptosis by selective inhibition of focal adhesion signaling may represent a novel anti-AML therapy. Here, we have evaluated the antitumor effect and the mechanism of action of celecoxib and E7123, a non-Cox-2 inhibitor derivative, in a panel of human AML cell lines and bone marrow mononuclear cells from AML patients. Both compounds induce cell death by inhibiting focal adhesion signaling through p130Cas, FAK and c-Src, leading to caspase-8 dependent apoptosis. This mechanism of action differs from that of classical cytotoxic drugs or of other targeted therapies, and is amenable to rational drug development. Therefore, both drugs could be developed as AML therapeutics; nevertheless, E7123 shows more activity than celecoxib against AML cells, and may not present its Cox-2 dependent cardiovascular toxicity. Finally, our results support the evaluation of celecoxib in AML patients, and the preclinical evaluation of E7123, before its possible clinical testing. ' 2008 Wiley-Liss, Inc.Key words: celecoxib derivative; AML; focal adhesions; p130Cas; caspase-8 Despite significant advances in the epidemiological, genetic and biological understanding of acute myeloid leukemia (AML), its basic therapeutic approach has not substantially changed for the last 10-15 years, so that today most patients still die of their disease. First-line chemotherapy with cytarabine and an anthracycline induces 70-80% of complete remissions; however, relapse after chemotherapy and poor response to subsequent therapy lead to only 30-50% long-term disease-free survival. 1 The use of new agents and procedures, or high doses of old agents, have failed to substantially improve this outcome. 2 Enhanced survival in AML patients depends, therefore, on the development of drugs with new mechanisms of action.Our group is focusing on the development of antitumor drugs that induce apoptosis by inhibiting focal adhesion signaling. Engagement of integrins (VLA-4, VLA-5) or chemokine receptors (CXCR4, c-Kit) in hematopoietic stem cells (HSC) leads to enhanced phosphorylation and signaling through focal adhesion components, including p130Cas, FAK and Src family proteins, [3][4][5] and influence their retention and release into circulation. 6,7 When HSC transform into AML blasts, they show enhanced anchorage independent growth, associated with the constitutive activation of focal adhesion proteins, as it happens during transformation in solid tumors. 8 Thus, AML genetic alterations (FLT3, c-Kit, CXCR4) lead not only to a failure in HSC differentiation and blast overproliferation, but also to abnormal migration and focal adhesion deregulation. 7 These genetic mutations are associated with overexpression o...
FAK expression is an independent prognostic factor in DLBCL. Our results suggest that the addition of FAK immunostaining to the current immunohistochemical algorithms may facilitate risk stratification of DLBCL patients.
In normal B-cells, B-cell antigen receptor (BCR) signaling can be negatively regulated by the low-affinity receptor FcγRIIb (CD32b). To better understand the role of FcγRIIb in chronic lymphocytic leukemia (CLL), we correlated its expression on 155 samples from newly-diagnosed Binet A patients with clinical characteristics and outcome. FcγRIIb expression was similar in normal B-cells and leukemic cells, this being heterogenous among patients and within CLL clones. FcγRIIb expression did not correlate with well known prognostic markers [disease stage, serum beta-2 microglobulin (B2M), IGHV mutational status, expression of ZAP-70 and CD38, and cytogenetics] except for a weak concordance with CD49d Moreover, patients with low FcγRIIb expression (69/155, 44.5%) required therapy earlier than those with high FcγRIIb expression (86/155, 55.5%) (median 151.4 months vs. not reached; p=0.071). These results encourage further investigation on the role of FcγRIIb in CLL biology and prognostic significance in larger series of patients.
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