Chronic graft-versus-host disease (cGVHD) causes significant morbidity and mortality in patients otherwise cured of malignancy after hematopoietic stem cell transplantation (HSCT). The presence of alloantibodies and high plasma B cell–activating factor (BAFF) levels in patients with cGVHD suggest that B cells play a role in disease pathogenesis. We performed detailed phenotypic and functional analyses of peripheral B cells in 82 patients after HSCT. Patients with cGVHD had significantly higher BAFF/B-cell ratios compared with patients without cGVHD or healthy donors. In cGVHD, increasing BAFF concentrations correlated with increased numbers of circulating pre–germinal center (GC) B cells and post-GC “plasmablast-like” cells, suggesting in vivo BAFF dependence of these 2 CD27+ B-cell subsets. Circulating CD27+ B cells in cGVHD comprised in vivo activated B cells capable of IgG production without requiring additional antigen stimulation. Serial studies revealed that patients who subsequently developed cGVHD had delayed reconstitution of naive B cells despite persistent BAFF elevation as well as proportional increase in CD27+ B cells in the first year after HSCT. These studies delineate specific abnormalities of B-cell homeostasis in patients with cGVHD and suggest that BAFF targeting agents may be useful in this disease.

HIV-1-based lentiviral vectors are a promising tool for gene therapy. However, integration of a lentiviral vector into host cell genes may lead to the development of cancer. Therefore, control of integration site selection is critical to the successful outcome of gene therapy approaches that use these vectors. The discovery that integration site selection by HIV-1 and HIV-1-based vectors is controlled by the LEDGF=p75 protein has presented new opportunities to control integration site selection. In this study, we tested the hypothesis that a fusion protein containing the C-terminal HIV integrase-binding portion of LEDGF=p75, and the N-terminal chromodomain of heterochromatin protein-1a (HP1a), can target HIV-1 vector DNA outside of genes. We show that this fusion protein, termed TIHPLE, associates with the heterochromatin hallmark trimethylated Lys-9 of histone H3 (H3K9me3). Transient overexpression of TIHPLE alters integration site selection by an HIV-1-based vector and decreases the number of integration events that occur in genes. This change in integration site selection was achieved without a reduction in overall integration efficiency. Furthermore, we show that TIHPLE increases integration in the vicinity of H3K9me3 and in repetitive DNA sequences. These data provide a novel approach to address the problem of the tendency of retroviral vectors to integrate at undesirable sites of the human genome.

CD30ϩ lymphoproliferative disorders represent a spectrum of diseases with distinct clinical phenotypes ranging from reactive conditions to aggressive systemic anaplastic lymphoma kinase (ALK)Ϫ anaplastic large cell lymphoma (ALCL). In January 2011, the U.S. Food and Drug Administration (FDA) announced a possible association between breast implants and ALCL, which was likened to systemic ALCL and treated accordingly. We analyzed existing data to see if implant-associated ALCL (iALCL) may represent a distinct entity, different from aggressive ALCL. We conducted a systematic review of publications regarding ALCL and breast implantation for 1990 -2012 and contacted corresponding authors to obtain long-term follow-up where available. We identified 44 unique cases of iALCL, the majority of which were associated with seroma, had an ALK Ϫ phenotype (97%), and had a good prognosis, different from the expected 40% 5-year survival rate of patients with ALK Ϫ nodal ALCL (one case remitted spontaneously following implant removal; only two deaths have been reported to the FDA or in the scientific literature since 1990). The majority of these patients received cyclophosphamide, doxorubicin, vincristine, and prednisolone with or without radiation, but radiation alone also resulted in complete clinical responses. It appears that iALCL demonstrates a strong association with breast implants, a waxing and waning course, and an overall good prognosis, with morphology, cytokine profile, and biological behavior similar to those of primary cutaneous ALCL. Taken together, these data are suggestive that iALCL may start as a reactive process with the potential to progress and acquire an aggressive phenotype typical of its systemic counterpart. A larger analysis and prospective evaluation and follow-up of iALCL patients are necessary to definitively resolve the issue of the natural course of the disease and best therapeutic approaches for these patients. The Oncologist 2013;18:301-307Implications for Practice: Breast implant -associated anaplastic large cell lymphoma (iALCL) is a relatively new and rare entity.Since it was first described in the 1990s it has been treated with aggressive therapies, similar to cutaneous lymphomas until they were designated to their own treatment category. This review demonstrates the similarities of iALCL to primary cutaneous ALCL by its good prognosis, biologic behavior, morphology, and relapsing nature. A larger analysis with prospective evaluation and follow-up of iALCL patients is necessary to definitively resolve the issue of the natural course and best therapeutic approaches for these patients. Less aggressive therapeutic options may be used in the future but this cannot be recommended without further investigation and clinical trials. INTRODUCTION Learning ObjectivesDescribe the spectrum of diseases, represented by CD30 ϩ lymphoproliferative disorders (LPDs), that can give rise to a reactive process. Discuss the favorable prognoses of reactive CD30ϩ LPDs and how they do not therefore require...

Excessive levels of B Cell Activating Factor (BAFF) are found in patients with active chronic graft versus host disease (cGVHD). In mice, BAFF has been shown to be essential for B cell recovery after myeloablation. To assess how BAFF levels relate to transplant factors and subsequent cGVHD development, we prospectively monitored 412 patients in the first year after allogeneic peripheral blood or bone marrow (PB/BM) hematopoietic stem cell transplantation (HSCT) and censoreddata at time ofcGVHD onset. In patients who did not develop cGVHD, we affirmeda temporal pattern of gradual BAFF level decreaseas theB cell numbers increase after myeloablative conditioning (MAC). By contrast, after reduced intensity conditioning (RIC), BAFF levels remained high throughoutthe first post-HSCT year, suggesting that the degree of myeloablation resulted in delayedB cell recovery associated with persistence of higher BAFF levels. Since high BAFF/B ratios have been associated with active cGVHD, weexamined differences in early BAFF/B ratios and found significantly different BAFF/B ratios at 3 months post-HSCT only afterMAC in patients who subsequently developed cGVHD. In addition toHSCT conditioning type, use of sirolimus was significantly associated with higher BAFF levels after HSCT and this wasalso potentially related tolower B cell numbers. Together, our results are important for interpretation of BAFF measurements in cGVHD biomarker studies.