Upregulation of inflammatory cytokines and oncogenic signal pathways preceding tumor formation in a murine model of T-cell lymphoma in skin.

The tumor microenvironment, including its inflammatory components, regulates tumor progression. Herein, we explore the relationship between inflammation and the progression of T-cell lymphoma in the cutaneous microenvironment. Injection of MBL2 murine T lymphoma cells into ear skin of C57BL/6 and immunodeficient SCID/Beige mice resulted in tumor formation in only the latter group. However, induction of skin inflammation by one topical application of DNFB following MBL2 inoculation in C57BL/6 mice resulted in progressive high-grade lymphoma. The DNFB-regulated tumor formation was blocked by early, but not late, application of a potent topical corticosteroid. At 2 days after implantation, a 10-fold decrease in MBL2 cell apoptosis was detected in DNFB-treated ears compared with vehicle control. After DNFB treatment, Gr-1(high) neutrophils and F4/80(+) macrophages constituted the majority of tumor-infiltrating CD45(+) leukocytes. Depletion of macrophages by clodronate-containing liposomes blocked the tumor-promoting effect of DNFB. Transcriptional profiling of inflammatory cytokines and chemokines after DNFB treatment revealed robust changes in genes that are important in chemotaxis, proliferation, and apoptosis. Activation of oncogenic signal pathways, including NF-κB, was also detected. This work provides insights into the cellular and molecular pathways that mediate lymphoma progression and may have applicability to human cutaneous T-cell lymphomas.

Paradoxical increase in skin inflammation in the absence of CCR4.

The chemokine receptors are seven transmembrane, G-protein-coupled surface receptors that play key roles in the migration and localization of leukocytes to the skin during physiologic and inflammatory states. Their ligands, chemokines, are small secreted proteins that initiate leukocyte chemoattraction. Recent data indicate that known subsets of T helper (Th) cells express signature chemokine receptors (e.g., CXCR3, CCR3/4, and CCR6) that help to define individual subsets such as Th1, Th2, and Th17 cells, respectively, although there is some degree of overlap among these T-cell subsets. In this issue, Lehtimäki et al. use an oxazolone-induced contact hypersensitivity (CHS) model to show that T cells (as well as neutrophils and eosinophils) from CCR4(-/-) mice accumulate just as (if not more) efficiently in inflamed skin as compared with the same population of leukocytes from wild-type (WT) mice. Although somewhat unexpected, their results can be explained if CCR4 attracts both proinflammatory and suppressive T cells into skin in addition to serving functions that are partially redundant with those of CCR10. Finally, we discuss other possible roles for CCR4 in the homing of T cells to skin.

Recurrent deep vein thrombosis and pulmonary embolism in a young man with Klinefelter's syndrome and heterozygous mutation of MTHFR-677C>T and 1298A>C.

Klinefelter's syndrome is characterized by hypogonadism and infertility and commonly has an XXY karyotype. Within the population of men with this disorder, there is an increased incidence of venous thromboembolic disease. Although the precise mechanisms underlying this prothrombotic state have not been elucidated, it is thought that the increased incidence of thromboembolism is associated with a hypofibrinolytic state secondary to androgen deficiency. We present the case of a 26-year-old man with Klinefelter's syndrome who had recurrent episodes of deep venous thrombosis and pulmonary embolism while undergoing therapeutic anticoagulation. Coagulation studies were significant for the heterozygous mutations of MTHFR-677C>T and 1298A>C gene and hyperhomocystenemia. Our aim is to raise awareness of this association and discuss management for these patients.

Ewing's sarcoma of the kidney.

Primitive neuroectodermal tumors (PNETs) are small, round-cell tumors of neural crest origin classically found in the central nervous system (CNS) but more recently characterized in the periphery. Peripherally located PNETs (pPNETs) are members of the Ewing's sarcoma family of tumors (EFTs). Renal localization of pPNETs is very rare, is found in young adults, and is characterized by an aggressive clinical course and poor prognosis. We present the case of a young man with renal pPNET characterized by psuedorosette formation, cluster of differentiation 99 (CD 99+), focally positive for neuron-specific enolase (NSE), with cytogenetic findings of the translocation t(11;22)(q24;q12) and the unique abnormality of trisomy 7. To our knowledge, we report the first case of trisomy 7 and PNET.

Histone deacetylase inhibitors induce apoptosis with minimal viral reactivation in cells infected with Kaposi's sarcoma-associated herpesvirus.

Kaposi's sarcoma-associated herpesvirus (KSHV) latently infects tumor cells in patients with Kaposi's sarcoma and primary effusion lymphoma (PEL). The purpose of this study was to determine whether histone deacetylase inhibitors (HDAI) could induce apoptosis, with minimal viral replication, in cells latently infected with KSHV. Four HDAI (depsipeptide, suberoylanilide hydroxamic acid, MS-275, and trichostatin A) were studied in two PEL B cell lines (BCBL-1, BC-3). As expected, histone hyperacetylation was readily induced in all PEL cells exposed to HDAI. HDAI also triggered KSHV reactivation in a time- and dose-dependent manner. Flow cytometric and transmission electron microscopic studies, however, revealed that reactivation occurred in only a minor percentage (3-14%) of treated cells. Importantly, and in contrast to viral reactivation, HDAI induced apoptotic cell death in a dose-dependent manner in a large percentage (up to 90%) of KSHV-infected cells. In summary, all four HDAI tested induced histone hyperacetylation in all cells, KSHV reactivation in a minority of cells, and apoptotic cell death in a majority of cells latently infected with KSHV. These findings suggest that HDAI may be a therapeutic option for patients with KSHV-mediated diseases by rendering cells infected with KSHV susceptible to apoptosis.