Downregulated Expression of SHP-1 in Burkitt Lymphomas and Germinal Center B Lymphocytes

Abstract

We wish to identify developmental changes in germinal center B cells that may contribute to their rapid growth. SHP-1 is an SH2 domain–containing phosphotyrosine phosphatase that negatively regulates activation of B cells and other cells of hematopoietic lineages. We have found that in all 13 EBV-negative and 11 EBV-positive Burkitt lymphomas with a nonlymphoblastoid phenotype, the mean concentration of SHP-1 was reduced to 5% of that of normal B and T cells. The possibility that this diminished expression of SHP-1 was related to the germinal center phenotype of Burkitt lymphomas was supported by the low to absent immunofluorescent staining for SHP-1 in germinal centers, and by the inverse relationship between the concentration of SHP-1 and the expression of the germinal center marker CD38 on purified tonsillar B cells. In CD38-high B cells, SHP-1 concentration was 20% of that of mantle zone B cells from the same donor. This reduction in SHP-1 is comparable to that of cells from motheaten viable mev/mev mice in which there is dysregulated, spontaneous signaling by cytokine and antigen receptors. Therefore, germinal center B cells may have a developmentally regulated, low threshold for cellular activation.

Human T cell lymphotropic virus type I genomic expression and impact on intracellular signaling pathways during neurodegenerative disease and leukemia

“…Similar down-regulation has also been documented in Burkitts' lymphomas and germinal center B lymphocytes (223). These observations suggest that the constitutively activated IL-2 signal pathway (resulting either from the IL-2/IL-2R alpha autocrine loop or from the HTLV-Iassociated constitutive phosphorylation of JAK/STAT proteins) plays a key role in T cell transformation, and SHP-1 acts as a negative regulator of the IL-2 signal transduction pathway.…”

SHP-1 expression in peripheral T cells from patients with Sezary syndrome and in the T cell line HUT-78: implications in JAK3-mediated signaling

“…Previous studies in SHP-1-deficient B cell lines show that SHP-1 expression can be modulated by stimulation with phorbol ester (PMA). 18 In contrast, a similar stimulation failed to revert SHP-1 expression in some SHP-1-deficient T cell lymphoma lines, indicating either structural abnormalities of the SHP-1 gene due to methylation of the SHP-1 promoter, 20 or a lack of SHP-1 mRNA splicing in certain T cell lymphomas and myeloid leukemias. 27 Our finding of low mRNA SHP-1 content, not only in HUT-78 but also in SS patients, would be compatible with a functional in vivo blockade of gene transcription or mRNA instability.…”

“…3,13 In humans, a down-regulated SHP-1 expression has been reported under physiological conditions in B centroblasts pur-ified from germinal centers, and in their malignant counterparts from Burkitt lymphomas. 18 Also, a defective expression of SHP-1 has been documented in the myeloproliferative disorder polycythemia vera, 19 suggesting a role for SHP-1 as a negative regulator of the erythropoietin-receptor (Epo-R)/JAK2 signaling pathway. 7 A low expression of SHP-1 was initially related with HTLV-I transformed T cell lines, 11 but it has subsequently been reported in T cell lines derived from T cell lymphomas (HTLV-I positive or negative) and cutaneous T cell lymphomas (CTCL).…”

Role of the tyrosine phosphatase SHP-1 in K562 cell differentiation

“…In this regard, our results are analogous to recent studies in which SHP-1 expression was restored to Burkitt's lymphoma cells and increased B lymphocytic differentiation was observed. 45 However, it is important to note that expressing SHP-1 in K562 cells does not induce all aspects of the differentiated phenotype; for example, although transfected cells exhibit the increased adherence characteristic of more mature myeloid cells, they do not exhibit the typical morphology of these cells (as is seen following TPA induction). It will be important to determine in future work whether SHP-1 expression lowers the threshold for differentiation in response to myeloid inducers such as TPA.…”