Expression of SHP-1 Phosphatase Indicates Post-Germinal Center Cell Derivation of B-Cell Posttransplant Lymphoproliferative Disorders

Abstract

SUMMARY: SHP-1 tyrosine phosphatase acts as a negative regulator of signaling by receptors for growth factors, cytokines, and chemokines and by receptors involved in immune response. Our recent study showed that SHP-1 is tightly regulated at various stages of B-cell differentiation and is expressed in the mantle and marginal zones, interfollicular B cells, and plasma cells, whereas it is nondetectable in germinal center cells. In this study we evaluated expression of SHP-1 in vitro and in vivo in nine cell lines representing three different types of EBV ϩ B-cell populations closely resembling or derived from posttransplant lymphoproliferative disorders (PTLDs). Furthermore, we examined tissue samples from 58 patients with B-cell PTLDs, both EBV ϩ (85% of the cases analyzed) and EBV Ϫ (15%). SHP-1 protein was strongly expressed in all cell lines and PTLD cases. In addition, the PTLD cases were essentially negative for germinal center B-cell markers: none expressed CD10 and only one expressed BCL-6. More than 40% expressed a late post-germinal B-cell marker, CD138. The universal expression of SHP-1, lack of expression of CD10 and BCL-6, and frequent expression of CD138 suggest that PTLDs are derived from post-germinal center B cells regardless of the EBV cell infection status. Based on the immunophenotype, B-cell PTLDs could be divided into two broad categories corresponding to the early (CD10 Ϫ /BCL-6 Ϫ /SHP-1 ϩ /CD138 Ϫ ) and late (CD10 Ϫ /BCL-6 Ϫ /SHP-1 ϩ /CD138 ϩ ) postgerminal center cells. By being expressed earlier, SHP-1 is a more sensitive marker of post-germinal center B cells than CD138, which is seen on the terminally differentiated immunoblasts and plasma cells. (Lab Invest 2002, 82:1599 -1606.

TIMP1 induces CD44 expression and the activation and nuclear translocation of SHP1 during the late centrocyte/post-germinal center B cell differentiation

“…However, it is down-regulated in normal germinal center (GC) B lymphocytes and Burkitt lymphoma (BL) cells [20]. These data suggest that SHP1 expression is not only tightly regulated during B cell differentiation, but also reflects histogenesis of malignant lymphomas [21,22]. Furthermore, the induction of SHP1 expression leads to hematopoietic cell differentiation and adhesion in HL60, K562, and BL cell lines [23,24].…”

Molecular histogenesis of posttransplantation lymphoproliferative disorders

“…20,22 The post-GC origin of a significant fraction of PTLDs is also documented by expression of the Src homology 2-containing protein phosphatase 1, which associates with post-GC B cells. 44 A sizeable subset of monoclonal B-cell PTLDs arising from GC-related B cells is characterized by detection solely of nonfunctional rearrangements of IgV H genes and/or IgV L genes. Crippling mutations, introducing a stop codon in a previously functional rearrangement, account for the majority of these sterile rearrangements in IgV H and/or IgV L genes of PTLDs and abrogate Ig expression in the lymphoma clone.…”

Analysis of immunoglobulin heavy and light chain variable genes in post‐transplant lymphoproliferative disorders

“…Analysis of genotypic and of phenotypic markers of B-cell histogenesis has recently documented that the vast majority of PTLD derive from GC-experienced B-cells, independent of type of transplanted organ, interval between transplant and lymphoma, histology, EBV infection status and site of origin of the lymphoma [4,[16][17][18][19]. Despite a common origin from GC-experienced B-cells, however, PTLD reflect heterogeneous stages of B-cell maturation and immunological competence.…”