Abstract

SHP-1 and SOCS-1 are members of a family of negative regulators of signaling that act downstream of cytokine receptors, receptor tyrosine kinases and receptor complexes of the immune and hemopoietic system. SHP-1 and SOCS-1 act through the inhibition of the JAK2/STAT pathway and their inactivation is considered to be a relevant mechanism in JAK2/STAT pathway induction. Several observations point to induction of the JAK/STAT pathway as an important mechanism of lymphomagenesis. Since DNA methylation is a mechanism of gene silencing involved in the pathogenesis of human cancers, including lymphoma, here we tested the involvement of SHP-1 and SOCS-1 methylation in immunodeficiency-related lymphoma. Tumor samples from 34 HIV-related non-Hodgkin lymphoma (HIV-NHL) and 25 post-transplant lymphoproliferative disorders (PTLD) were analyzed for SOCS-1 and SHP-1 methylation by methylation-specific polymerase chain reaction. The tumor panel included 15 HIV-diffuse large B cell lymphoma (HIV-DLBCL), 10 HIV-Burkitt lymphoma (HIV-BL), 9 HIV-primary effusion lymphoma (HIV-PEL), 10 PTLD-immunoblastic (PTLD-IB), 7 PTLD-centroblastic (PTLD-CB), 4 polymorphic PTLD (P-PTLD), 3 PTLD-BL and 1 PTLD multiple myeloma (MM). Among HIV-NHL, SHP-1 methylation occurred in 23/34 (67%) cases, including 12/15 (80%) HIV-DLBCL, 4/10 (40%) HIV-BL, and 7/9 (78%) HIV-PEL. SOCS-1 methylation occurred in 6/34 (17%) HIV-NHL, including 5/9 (55%) HIV-PEL and 1/15 (7%) HIV-DLBCL. When considering EBV status, SHP-1 was methylated in 10/11 (91%) EBV-negative HIV-NHL and in 12/22 (54%) EBV-positive HIV-NHL. Among PTLD, SHP-1 methylation was detected in 20/25 (80%) cases, including 7/10 (70%) PTLD-IB, 6/7 (86%) PTLD-CB, 3/4 (75%) P-PTLD, 2/3 (66%) PTLD-BL and 1 PTLD MM. SOCS-1 methylation was detected in 3/25 (12%) PTLD, including 1/10 (10%) PTLD-IB and 2/7 (28%) PTLD-CB. When considering EBV status, SHP-1 was methylated in 12/13 (92%) EBV-negative PTLD and in 6/11 (54%) EBV-positive PTLD. The implications of our data are threefold. First, SHP-1 methylation is involved in the majority of HIV-NHL and PTLD. Second, it is remarkable that virtually all EBV-negative HIV-NHL and PTLD carry SHP-1 methylation. In EBV-positive B-cells, EBV infection activates the STAT pathway. It is conceivable that, in EBV-negative HIV-NHL and in EBV-negative PTLD, SHP-1 inactivation through aberrant methylation may surrogate EBV infection for STAT activation. Third, similar to observations in NHL of the immunocompetent host, SOCS-1 methylation is rarely implicated in the pathogenesis of immunodeficiency-related NHL. This notion is supported by the phenotype of SOCS1-deficient mice, that die of a myeloproliferative disease but do not develop a lymphoproliferative disease.

Disclosure: No relevant conflicts of interest to declare.

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