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BackgroundBRCA1–associated protein 1 (BAP1) is a tumor suppressor gene located on chromosome 3p21. Germline BAP1 mutations have been recently associated with an increased risk of malignant mesothelioma, atypical melanocytic tumors and other neoplasms. To answer the question if different germline BAP1 mutations may predispose to a single syndrome with a wide phenotypic range or to distinct syndromes, we investigated the presence of melanocytic tumors in two unrelated families (L and W) with germline BAP1 mutations and increased risk of malignant mesothelioma.MethodsSuspicious cutaneous lesions were clinically and pathologically characterized and compared to those present in other families carrying BAP1 mutations. We then conducted a meta-analysis of all the studies reporting BAP1-mutated families to survey cancer risk related to the germline BAP1 mutation (means were compared using t-test and proportions were compared with Pearson χ2 test or two-tailed Fisher’s exact test).ResultsMelanocytic tumors: of the five members of the L family studied, four (80%) carried a germline BAP1 mutation (p.Gln684*) and also presented one or more atypical melanocytic tumors; of the seven members of W family studied, all carried a germline BAP1 mutation (p.Pro147fs*48) and four of them (57%) presented one or more atypical melanocytic tumors, that we propose to call “melanocytic BAP1-mutated atypical intradermal tumors” (MBAITs). Meta-analysis: 118 individuals from seven unrelated families were selected and divided into a BAP1-mutated cohort and a BAP1-non-mutated cohort. Malignant mesothelioma, uveal melanoma, cutaneous melanoma, and MBAITs prevalence was significantly higher in the BAP1-mutated cohort (p ≤ 0.001).ConclusionsGermline BAP1 mutations are associated with a novel cancer syndrome characterized by malignant mesothelioma, uveal melanoma, cutaneous melanoma and MBAITs, and possibly by other cancers. MBAITs provide physicians with a marker to identify individuals who may carry germline BAP1 mutations and thus are at high risk of developing associated cancers.

Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, is invariably present in Kaposi's sarcoma lesions. KSHV contains several viral oncogenes and serological evidence suggests that KSHV infection is necessary for the development of Kaposi's sarcoma, but cellular transformation by this virus has not so far been demonstrated. KSHV is found in the microvascular endothelial cells in Kaposi's sarcoma lesions and in the spindle 'tumour' cells, which are also thought to be of endothelial origin. Here we investigate the biological consequences of infecting human primary endothelial cells with purified KSHV particles. We find that infection causes long-term proliferation and survival of these cells, which are associated with the acquisition of telomerase activity and anchorage-independent growth. KSHV was present in only a subset of cells, and paracrine mechanisms were found to be responsible for the survival of uninfected cells. Their survival may have been mediated by upregulation of a receptor for vascular endothelial growth factor. Our results indicate that transformation of endothelial cells by KSHV, as well as paracrine mechanisms that are induced by this virus, may be critical in the pathogenesis of Kaposi's sarcoma.

Primary effusion lymphoma (PEL) is a unique form of non-Hodgkin lymphoma (NHL) associated with Kaposi sarcoma-associated herpesvirus (KSHV; HHV-8) that displays a distinct constellation of clinical, morphologic, immunologic, and molecular characteristics. Rare KSHV-containing immunoblastic lymphomas occurring in solid tissues have been described. Whether they represent part of the spectrum of PEL has not been determined. The morphologic, immunophenotypic, and molecular features of KSHV-positive solid lymphomas occurring in 8 HIV+/AIDS patients were systematically investigated and compared with those of 29 similarly analyzed PELs. The 8 KSHV-positive solid lymphomas were virtually indistinguishable from the 29 PELs based on morphology (immunoblastic/anaplastic), immunophenotype (CD45 positive; T cell antigen negative; CD30, EMA, CD138 positive; CD10, CD15, BCL6 negative) and genotype (100% immunoglobulin genes rearranged; no identifiable abnormalities in C-MYC, BCL6, BCL1, BCL2; and uniformly EBV positive). The only identifiable phenotypic difference was that the KSHV-positive solid lymphomas appeared to express B cell-associated antigens (25%) and immunoglobulin (25%) slightly more often than the PELs (<5% and 15%, respectively; P = 0.11 and P = 0.08, respectively). The clinical presentation and course of the patients who develop KSHV-positive solid lymphomas were also similar, except for the lack of an effusion and somewhat better survival (median 11 months vs. 3 months). However, the 3 KSHV-positive solid lymphoma patients alive without disease 11, 25, and 44 months following initial presentation were recently diagnosed patients and, unlike the other patients with KSHV-positive solid lymphomas, received anti-retroviral therapy. These findings strongly suggest that these decidedly rare KSHV-positive solid lymphomas belong to the spectrum of PEL. Therefore, we propose that the KSHV-positive solid lymphomas be designated extra-cavitary PELs.

IntroductionClassical Hodgkin lymphoma (HL) is a lymphoid neoplasm that stems from the clonal expansion of mononuclear Hodgkin cells and multinuclear Reed-Sternberg cells expressing the CD30 antigen. 1 Malignant Hodgkin and Reed-Sternberg (HRS) cells usually constitute less than 10% of the neoplastic mass. 2 The remaining tissue is composed of a reactive cellular infiltrate. Although rare cases with T-cell genotype have been described, 3,4 the vast majority of classical HL tumors is thought to originate from transformed germinal center (GC) B cells, because their HRS component harbors a monoclonal immunoglobulin (Ig) gene rearrangement and somatically mutated Ig V region genes. 1,[5][6][7] Despite their GC B-cell origin, HRS cells lack many molecules usually expressed by B cells and are incapable of producing functional Igs. [7][8][9][10][11][12] While nonmalignant B cells that have lost their capacity to express Igs rapidly undergo apoptosis, 13 malignant HRS cells survive. This abnormal survival is thought to be due to dysregulated activation of nuclear factor B (NF-B), 14-18 a transcription factor essential for the development of both normal and neoplastic B cells. 19,20 In classical HL, the reactive infiltrate is composed of nonmalignant T cells, B cells, plasma cells, and myeloid cells, including macrophages and granulocytes. 2,21 These cells are thought to enhance HRS cell growth through cytokines and tumor necrosis factor (TNF) family members, such as CD30 ligand (CD30L), receptor activator of NF-B ligand (RANKL), and CD40 ligand (CD40L). 15,[22][23][24][25][26][27][28][29] Recent studies show that myeloid cells express B-cell-activating factor of the TNF family (BAFF, also known as BLyS) and its homolog APRIL, a proliferation-inducing ligand, [30][31][32][33] 2 molecules essential for the survival, proliferation, and differentiation of B cells and plasma cells. 34,35 BAFF activates B cells and plasma cells by binding to transmembrane activator and calcium modulator and cyclophylin ligand interactor (TACI), B-cell maturation antigen (BCMA), and BAFF receptor (BAFF-R) receptors. APRIL activates B cells and plasma cells by binding to TACI and BCMA, but not BAFF-R. 36 By recruiting TNF receptor-associated factor (TRAF) adaptor molecules, TACI, BCMA, and BAFF-R activate an IB kinase (IKK) complex that in turn elicits phosphorylation-dependent degradation of inhibitor of NF-B (IB), which retains p50, c-Rel, and p65 NF-B proteins in a cytoplasmic inactive form. [37][38][39] IB degradation causes NF-B nuclear translocation and transcriptional activation of NF-B-responsive genes involved in B-cell survival, proliferation, and maturation. 31,[39][40][41] Of note, recent studies show that APRIL signaling via TACI and BCMA receptors is reinforced by heparan sulfate proteoglycans (HSPGs) anchored on the cell membrane or associated with the extracellular matrix. 35,42,43 The role of TACI, BCMA, BAFF-R, and HSPGs in HL remains unknown.BAFF and APRIL are implicated in B-cell neoplasias, 44-52 including non-Hodgkin lymph...

HOXA9, and MEIS1 have essential oncogenic roles in mixed lineage leukaemia (MLL)-rearranged leukaemia. Here we show that they are direct targets of miRNA-196b, a microRNA (miRNA) located adjacent to and co-expressed with HOXA9, in MLL-rearranged leukaemic cells. Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression. However, ectopic expression of miR-196b results in more aggressive leukaemic phenotypes and causes much faster leukemogenesis in secondary transplantation than MLL fusion alone, likely through the further repression of Fas expression, a proapoptotic gene downregulated in MLL-rearranged leukaemia. Overexpression of FAS significantly inhibits leukemogenesis and reverses miR-196b-mediated phenotypes. Targeting Hoxa9/Meis1 and Fas by miR-196b is probably also important for normal haematopoiesis. Thus, our results uncover a previously unappreciated miRNA-regulation mechanism by which a single miRNA may target both oncogenes and tumour suppressors, simultaneously, or, sequentially, in tumourigenesis and normal development per cell differentiation, indicating that miRNA regulation is much more complex than previously thought.

• Stromal OPN anchors leukemia cells in prodormancy BM niches.• Inhibiting this interaction leads dormant cells to proliferate, sensitizing them to chemotherapy.Malignant cells may evade death from cytotoxic agents if they are in a dormant state. The host microenvironment plays important roles in cancer progression, but how niches might control cancer cell dormancy is little understood. Here we show that osteopontin (OPN), an extracellular matrix molecule secreted by osteoblasts, can function to anchor leukemic blasts in anatomic locations supporting tumor dormancy. We demonstrate that acute lymphoblastic leukemia (ALL) cells specifically adhere to OPN in vitro and secrete OPN when localized to the endosteal niche in vivo. Using intravital microscopy to perform imaging studies of the calvarial bone marrow (BM) of xenografted mice, we show that OPN is highly expressed adjacent to dormant tumor cells within the marrow. Inhibition of the OPN-signaling axis significantly increases the leukemic cell Ki-67 proliferative index and leads to a twofold increase in tumor burden in treated mice. Moreover, using cell-cycle-dependent Ara-C chemotherapy to produce minimal residual disease (MRD) in leukemic mice, we show that OPN neutralization synergizes with Ara-C to reduce detectable BM MRD. Taken together, these data suggest that ALL interacts with extracellular OPN within the malignant BM, and that this interaction induces cell cycle exit in leukemic blasts, protecting them from cytotoxic chemotherapy. (Blood. 2013;121(24):4821-4831) IntroductionAcute lymphoblastic leukemia (ALL) in adults initially responds well to induction chemotherapy, with greater than 80% of patients attaining a complete remission (CR). Unfortunately, most initial CRs are short lived, and overall survival rate is only 30% to 40% for adults who are diagnosed before age 60 years.1 Although outcomes in the pediatric population are better, a significant number of patients still experience relapsed or refractory disease.2 Relapses in both populations are believed to be the outgrowth of minimal residual disease (MRD) that is not completely eliminated by chemotherapy. Indeed, it has been demonstrated that patients with the lowest levels of detectable MRD at CR have the best prognosis and least likelihood of relapse.2 Strategies to overcome resistance and reduce MRD may therefore have the potential to increase overall survival duration.Antiapoptotic signals from the host tissue microenvironment are increasingly recognized as important mechanisms of malignant cell survival against chemotherapy. Our previous work using the Nalm-6 model of ALL has shown that the bone marrow (BM) microenvironment plays a critical role in disease spread and in the dysregulation of normal hematopoiesis that occurs during leukemic growth. 3,4 To metastasize and outcompete native BM cells, leukemic cells co-opt normal signaling mechanisms within hematopoietic stem cell (HSC) niches. At least 2 distinct HSC niches, one perivascular and one endosteal (or bony), exist in the BM. 5 In t...

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