SHP-1 expression by malignant small B-cell lymphomas reflects the maturation stage of their normal B-cell counterparts.

SHP-1 is a protein phosphotyrosine phosphatase that plays an important role in modulating intracellular signaling, which regulates cell activation, proliferation, differentiation, and migration. It is a negative regulator of signal transduction induced by a number of cell receptors. Our immunohistochemical examination of paraffin-embedded reactive lymph nodes and lymphoid tissues revealed that B lymphocytes in follicle germinal centers do not express SHP-1. A weak staining of the B cells in the germinal center light zones was detected when an ultrasensitive amplification system was used. In contrast, normal B cells in mantle and marginal zones as well as interfollicular B lymphocytes and plasma cells displayed strong immunoreactivity. This pattern of SHP-1 expression was repeated in small B-cell lymphomas. All cases of mantle cell lymphoma (12 of 12), marginal zone lymphoma (10 of 10), and chronic lymphocytic leukemia/small lymphocytic lymphoma (13 of 13) expressed SHP-1 protein. However, only 1 of 30 cases of grade 1 follicle center cell lymphoma expressed SHP-1. Our observations highlight the biologic functions of SHP-1 and demonstrate that the SHP-1 expression pattern by small B-cell lymphomas reflects the maturation stage of their normal cell counterparts. These results indicate that determination of SHP-1 expression may help in the differential diagnosis of small B-cell lymphomas.

Bcl-2 expression restores the leukemogenic potential of a BCR/ABL mutant defective in transformation.

Growth factor-dependent hematopoietic cell lines expressing the BCR/ABL oncoprotein of the Ph chromosome show growth factor-independent proliferation and resistance to apoptosis. Apoptosis resistance of BCR/ABL-expressing cells may depend on enhanced expression of anti-apoptotic proteins as well as reduced expression and/or inactivation of pro-apoptotic proteins. Compared to myeloid precursor 32Dcl3 cells expressing wild type BCR/ABL, cells expressing a BCR/ABL mutant lacking amino acids 176-426 in the BCR domain (p185 delta BCR) are susceptible to apoptosis induced by interleukin-3 (IL-3) deprivation. These cells exhibited the hypophosphorylated apoptotic BAD and markedly reduced levels of Bcl-2. Upon ectopic expression of Bcl-2, these cells showed no changes in BAD phosphorylation, but they became apoptosis-resistant and proliferated in the absence of IL-3, albeit more slowly than cells expressing wild type BCR/ABL. Moreover, the p185 delta BCR/Bcl-2 double transfectants were leukemogenic when injected into immunodeficient mice, but Bcl-2 expression did not restore the leukemia-inducing effects of p185 delta BCR to the levels of wild type BCR/ABL. Leukemic cells recovered from the spleen of mice injected with p185 delta BCR/Bcl-2 cells did not show rearrangements in the Bcl-2 genomic locus, but they exhibited enhanced proliferation in culture and induced a rapidly fatal disease process when inoculated in secondary recipient mice. Together, these data support the importance of anti-apoptotic pathways for BCR/ABL-dependent leukemogenesis and suggest that Bcl-2 expression promotes secondary changes leading to a more aggressive tumor phenotype. (Blood. 2000;96:3915-3921)

The immunosuppressive macrolide RAD inhibits growth of human Epstein-Barr virus-transformed B lymphocytes in vitro and in vivo: A potential approach to prevention and treatment of posttransplant lymphoproliferative disorders.

Whereas the standard immunosuppressive agents foster development of posttransplant lymphoproliferative disorders (PTLDs), the impact of RAD, a macrolide with potent immunosuppressive properties, and other immunosuppressive macrolides on these disorders remains undetermined. We found that RAD had a profound inhibitory effect on in vitro growth of six different PTLD-like Epstein-Barr virus+ lymphoblastoid B cell lines. Similar to normal T cells, RAD blocked cell-cycle progression in PTLD-like B cells in the early (G(0)/G(1)) phase. Furthermore, RAD increased the apoptotic rate in such cells. The drug also had a profound inhibitory effect on the growth of PTLD-like Epstein-Barr virus+ B cells xenotransplanted s.c. into SCID mice. The degree of the RAD effect varied among the three B cell lines tested and was proportional to its effects on the cell lines in vitro. In this in vivo xenotransplant model, RAD markedly delayed growth or induced regression of the established tumors. In one line, it was able to eradicate the tumor in four of eight mice. When RAD treatment was initiated before tumor cell injection, a marked inhibition of tumor growth was seen in all three lines. In two of them, the drug prevented tumor establishment in approximately 50% of mice (5/11 and 5/8). In summary, RAD is a potent inhibitor of PTLD-like cells in vitro and in vivo. These findings indicate that, in contrast to the standard immunosuppressive agents, macrolides such as RAD may be effective in prevention and treatment of PTLDs.

Lymphoid lesions of the thyroid: review in light of the revised European-American lymphoma classification and upcoming World Health Organization classification.

Thyroid lymphomas are rare diseases and almost always rise in the background of chronic lymphocytic thyroiditis (Hashimoto's thyroiditis). Large cell lymphoma is an aggressive disease and usually is not a significant diagnostic challenge from the pathological point of view. Small cell lymphoma, however, can sometimes be difficult to distinguish from chronic lymphocytic thyroiditis. In the past, most thyroid lymphomas were considered to be of follicle center cell origin. Today, after the introduction of the mucosa-associated lymphoid tissue (MALT) and the extranodal lymphoid tissue (ELT) concepts, most of the lymphomas in the extranodal sites are thought to originate from the marginal zone of the lymphoid follicles. The distinction between the different types of lymphomas has significant impact on the patient's prognosis, treatment, and follow-up. It is imperative that clinicians (endocrinologists and surgeons) and pathologists are aware of these types of lymphomas in order for the most appropriate diagnostic procedures to be selected, specific staging principles to be applied, and appropriate disease-specific treatment to be implemented. It is also important that terms such as "lesion of uncertain malignant potential" as defined by ancillary studies be understood.

Role of xanthine oxidase-derived oxidants and leukocytes in ethanol-induced jejunal mucosal injury.

Previous reports indicate that intestinal intraluminal ethanol increases mucosal permeability (an index of mucosal injury) and histamine release by mast cells, and that the released histamine plays a role in mediating the increased permeability. In the present study, we investigated whether reactive oxygen metabolites and their major sources (xanthine oxidase and leukocytes) were involved in these ethanol effects. In rabbits, segments of the jejunum were perfused with a control solution or with 6% ethanol. In these segments, mucosal permeability was assessed by determining jejunal clearance of i.v. administered 51Cr-ethylenediaminetetraacetate (51Cr-EDTA) and 125I-bovine serum albumin (125I-BSA), and mast cell histamine release was estimated from the histamine concentration of the gut effluent. Ethanol increased 51Cr-EDTA clearance, 125I-BSA clearance, and histamine release. These ethanol effects decreased when the animals were given superoxide dismutase plus catalase (scavenger of O2- and H2O2, respectively), allopurinol, or oxypurinol (xanthine oxidase inhibitors). Administration of a monoclonal antibody (R15.7) against leukocyte adhesion molecule, CD18, inhibited completely the ethanol-induced increased 51Cr-EDTA and 125I-BSA clearances and histamine release. These and supplementary data suggest that (a) ethanol-induced mucosal injury and mast cell histamine release are mediated primarily by leukocytes, and (b) oxy radicals, especially those generated by xanthine oxidase, mediate these ethanol effects mainly by promoting leukocyte infiltration.

Adaptive cytoprotection against ethanol-induced small intestinal mucosal injury.

Exposure of the small intestinal mucose to 6% ethanol (which is found in human jejunum during alcohol consumption) causes morphological alterations, and increased permeability of the mucosa and histamine release from intestinal mast cells. The released histamine is shown to mediate a significant component of the increased mucosal permeability (i.e., mucosal injury). In the present study, we have investigated whether adaptive cytoprotection occurs against the increased mucosal permeability and histamine release induced by 6% ethanol. Rabbits were used. In each animal, three adjacent segments of upper small intestine were pre-perfused for 30 min, and then perfused for 90 min in the following order control solution followed by control solution (control segment); control solution followed by 6% ethanol (ethanol segment); 1% ethanol followed by 6% ethanol (pretreated ethanol segment). During the 90-min perfusion, mucosal permeability of each segment was measured by analyzing the effluent for intraluminal clearance of i.v. administered 51Cr-labelled ethylenediaminetetraacetic acid (51Cr-EDTA) and 125I-labelled bovine serum albumin (125I-BSA). Mast cell histamine release was assessed by determining histamine concentration of the gut effluent. All measurements were higher in the ethanol segments than in the controls. These ethanol effects were significantly lower in the pretreated ethanol segments, indicating that adaptive cytoprotection occurs against the mucosal injury induced by 6% ethanol. These findings are discussed in relation to the literature on mucosal effects of intestinal intraluminal ethanol.