CD117 expression in diffuse large B-cell lymphomas: Fact or fiction?

CD117 (KIT) is expressed in a variety of hematopoietic neo- plasms but there are a paucity of data regarding its expres- sion in diffuse large B-cell lymphomas (DLBCL). The purpose of the present paper was to describe the authors’ experience of two CD117+ DLBCL (one of follicle center-cell origin and one nasal Epstein–Barr virus (EBV)– plasmablas- tic lymphoma associated with lytic bone lesions), as deter- mined by tissue immunohistochemistry and flow cytometry. The CD117 expression in DLBCL was further evaluated using tissue microarrays and seven additional plasma- blastic lymphomas, using two commercially available anti-CD117 antibodies (Ab-1, Oncogene and A4502, Dako- Cytomation). Membranous ± cytoplasmic staining was seen with Ab-1 in 24/65 (37%) DLBCL, including 21/56 microarray DLBCL, two index cases, and 1/7 additional plasmablastic lymphomas, with persistent staining in 13% of microarray DLBCL despite preincubation with KIT peptide. However, A4502 had only membranous staining of the index cases and one additional EBV– plasmablastic lymphoma with medullary disease. The present study suggests that (i) CD117 expression can be detected sporadically in DLBCL of follicle center-cell origin and a subset of plasmablastic lymphomas; (ii) staining for CD117 might help in identifying EBV– plasmablastic lymphomas associated with bone mar- row involvement; and (iii) CD117 antibodies should be care- fully validated prior to use, because non-specific staining, as observed with Ab-1, could lead to false-positive results

Diffuse large B-cell lymphoma with TEL/ETV6 translocation

Cytogenetic abnormalities of chromosome 12p involving the TEL/ETV6 gene are observed in a variety of hematopoietic neoplasms including acute leukemias, myelodysplastic syndromes, and myeloproliferative disorders. Karyotypic aberrations, including rearrangements, deletions, and amplifications of chromosome 12p, have been documented in B-cell non-Hodgkin lymphoma; however, rearrangements targeting TEL have rarely been reported. Here we describe a diffuse large B- cell lymphoma that had a complex karyotype including t(9;12)(q22;p13), which was confirmed by fluorescence in situ hybridization to represent rearrangement of TEL. Additional cytogenetic abnormalities included t(3;14)(q27;q32) involving the variant, alternative breakpoint region of the BCL6 gene and del(6)(q13q23), resulting in the loss of 1 allele of BLIMP1. This case reiterates the importance of correlating morphologic and phenotypic findings with the results of cytogenetic analysis to avoid errors in diagnosing hematologic neoplasms and highlights the rare association of B-cell non- Hodgkin lymphoma with aberrations of TEL

CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to c-secretase inhibitors

Activating mutations in NOTCH1 are present in over 50% of human T-cell lymphoblastic leukemia (T-ALL) samples and inhibition of NOTCH1 signaling with c-secretase inhibitors (GSI) has emerged as a potential therapeutic strategy for the treatment of this disease. Here, we report a new human T-cell lymphoma line CUTLL1, which expresses high levels of activated NOTCH1 and is extremely sensitive to c-secretase inhibitors treatment. CUTLL1 cells harbor a t(7;9)(q34;q34) translocation which induces the expression of a TCRB-NOTCH1 fusion transcript encoding a membrane-bound truncated form of the NOTCH1 receptor. GSI treatment of CUTLL1 cells blocked NOTCH1 processing and caused rapid clearance of activated intracellular NOTCH1. Loss of NOTCH1 activity induced a gene expression signature characterized by the downregulation of NOTCH1 target genes such as HES1 and NOTCH3. In contrast with most human T-ALL cell lines with activating mutations in NOTCH1, CUTLL1 cells showed a robust cellular phenotype upon GSI treatment characterized by G1 cell cycle arrest and increased apoptosis. These results show that the CUTLL1 cell line has a strong dependence on NOTCH1 signaling for proliferation and survival and supports that T-ALL patients whose tumors harbor t(7;9) should be included in clinical trials testing the therapeutic efficacy NOTCH1 inhibition with GSIs. Leukemia (2006) 20, 1279–1287. doi:10.1038/sj.leu.2404258; published online 11 May 200

Immunoglobulin-like transcript 3: A crucial regulator of dendritic cell function

Dendritic cells (DC) are key components of the immune system, which actively participate in innate and adaptive immune responses. They are traditionally viewed as the immunologic centerpiece that is able to prime CD4 helper and CD8 cytotoxic T-cell effector populations. However, accumulated evidence highlights the functional plasticity of DC, which are shown to also be able to display a tolerogenic function eliciting the differentiation of T suppressor (Ts) and regulatory (Treg) cells. This tolerogenic state of DC is characterized by low costimulatory potential and high expression of inhibitory receptors. Conspicuously among the latter is the immunoglobulin-like transcript 3 (ILT3), which independently prevents the activation of both DC and T cells. DC overexpressing ILT3 display lower phosphorylation levels of NF-B and fail to stimulate the full program of Th proliferation and maturation eliciting instead the differentiation of CD8 TS and CD4 Treg. In contrast, ILT3-knockdown DC have robust cytokine and chemokine production, and are able to trigger stronger T-cell responses to viral antigens or alloantigens. Understanding and manipulating the functional immunogenic/tolerogenic dichotomy of DC has important clinical applications for achieving tolerance in organ transplantation, stemming autoimmune diseases or, conversely, generating efficient immunogenic vaccines for immunotherapy in cancer and chronic viral diseases

Suppression of xenogeneic graft-versus-host disease by treatment with immunoglobulin-like transcript 3-Fc

Allogeneic hematopoietic cell transplantation represents an important therapy for certain malignant and nonmalignant diseases. However, graft-versus-host disease (GVHD) is a major cause of mortality and morbidity. The search for agents that can efficiently suppress GVHD has been going on for more than half a century. GVHD is particularly strong in xenogeneic donor-recipient combinations, given the unlimited number of potentially immunogenic antigens donor lymphocytes encounter in the host. Using a hunonobese diabetic/severe combined immunodeficiency (hu-NOD/SCID) gamma-null model of xenogeneic GVHD, we have demonstrated that treatment with recombinant immunoglobulin-like transcript 3-Fc protein induces the differentiation of CD8(+) T suppressor cells and blocks the cellular and humoral arm of the GVH reaction. (C) 2009 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved