Role of Huntingtin Interacting Protein HIP-1 in Non-Hodgkin’s Lymphoma.

We have developed a murine model for mantle cell lymphoma (muMCL) that occurs after pristane injection of E_μ-cyclin D1 transgenic mice that are > 1 year of age (Leukemia 20:891, 2006). E_μ-cyclin D1 transgenic mice are healthy, implying that cyclin D1 may be necessary, but not sufficient, for MCL decvelopment. We are using this model to identify genes that coooperate with cyclin D1 in lymphomagenensis. Comparing gene expression in B cells from spleens of these muMCL with B cells from non-pristane injected age-matched E_μ-cyclin D1 transgenic mice by differential gene expression, we identified up-regulation of RNA for the Huntingtin interacting protein HIP-1 in the muMCL. We confirmed that this translated into up-regulation at the protein level by Western blot. HIP-1 is an inositol lipid, clathrin and actin binding protein that can directly transform fibroblasts. HIP-1, located on 7q, was previously found in a fusion protein with PDGFRβ in a case of CMML with t(5;7), suggsting a role in hematopoietic malignancies. To test the generalizability of the finding of HIP-1 overexpression in lymphoma, we performed immunohistochemistry using the monoclonal anti-HIP-1 antibody 4B10 on a lymphoma tissue microarray (Cybridi). Positive antibody staining was found in 79 of 116 (68.1%) non-Hodgkin’s lymphomas (NHL). Based on:

1. our identification of HIP-1 as a potential cooperating gene in MCL development;

2. overexpression of HIP-1 in many NHL; and

3. that the presence of antibodies to HIP-1 in serum correlates with overexpression of the protein, we tested serum samples from lymphoma patients.

We found circulating HIP-1 antibodies in sera from 23 of 39 (59%) lymphoma patients. The highest antibody titer was in serum from a patient with T-ALL in remission during maintenance chemotherapy who had a cytogenetic abnormality of 7q near the site of the HIP-1 gene. Studies are ongoing to expand this data set to see if HIP-1 antibodies correlate with disease type or outcome. In summary, HIP-1 appears to be involved in lymphoma development in a murine model of MCL and is frequently overexpressed in other types of NHL. Its role in lymphomagenesis, and potentially in treatment response and prognosis needs to be further explored.