AP-1 family transcription factors have been implicated in the control of proliferation, apoptosis and malignant transformation. However, their role in oncogenesis is unclear and no recurrent alterations of AP-1 activities have been described in human cancers. Here, we show that constitutively activated AP-1 with robust c-Jun and JunB overexpression is found in all tumor cells of patients with classical Hodgkin's disease. A similar AP-1 activation is present in anaplastic large cell lymphoma (ALCL), but is absent in other lymphoma types. Whereas c-Jun is up-regulated by an autoregulatory process, JunB is under control of NF-kappa B. Activated AP-1 supports proliferation of Hodgkin cells, while it suppresses apoptosis of ALCL cells. Furthermore, AP-1 cooperates with NF-kappa B and stimulates expression of the cell-cycle regulator cyclin D2, proto-oncogene c-met and the lymphocyte homing receptor CCR7, which are all strongly expressed in primary HRS cells. Together, these data suggest an important role of AP-1 in lymphoma pathogenesis.

B cell differentiation is controlled by a complex network of lineage-restricted transcription factors. How perturbations to this network alter B cell fate remains poorly understood. Here we show that classical Hodgkin lymphoma tumor cells, which originate from mature B cells, have lost the B cell phenotype as a result of aberrant expression of transcriptional regulators. The B cell-specific transcription factor program was disrupted by overexpression of the helix-loop-helix proteins ABF-1 and Id2. Both factors antagonized the function of the B cell-determining transcription factor E2A. As a result, expression of genes specific to B cells was lost and expression of genes not normally associated with the B lineage was upregulated. These data demonstrate the plasticity of mature human lymphoid cells and offer an explanation for the unique classical Hodgkin lymphoma phenotype.

Resistance to death receptor–mediated apoptosis is supposed to be important for the deregulated growth of B cell lymphoma. Hodgkin/Reed-Sternberg (HRS) cells, the malignant cells of classical Hodgkin's lymphoma (cHL), resist CD95-induced apoptosis. Therefore, we analyzed death receptor signaling, in particular the CD95 pathway, in these cells. High level CD95 expression allowed a rapid formation of the death-inducing signaling complex (DISC) containing Fas-associated death domain–containing protein (FADD), caspase-8, caspase-10, and most importantly, cellular FADD-like interleukin 1β–converting enzyme-inhibitory protein (c-FLIP). The immunohistochemical analysis of the DISC members revealed a strong expression of CD95 and c-FLIP overexpression in 55 out of 59 cases of cHL. FADD overexpression was detectable in several cases. Triggering of the CD95 pathway in HRS cells is indicated by the presence of CD95L in cells surrounding them as well as confocal microscopy showing c-FLIP predominantly localized at the cell membrane. Elevated c-FLIP expression in HRS cells depends on nuclear factor (NF)-κB. Despite expression of other NF-κB–dependent antiapoptotic proteins, the selective down-regulation of c-FLIP by small interfering RNA oligoribonucleotides was sufficient to sensitize HRS cells to CD95 and tumor necrosis factor–related apoptosis-inducing ligand–induced apoptosis. Therefore, c-FLIP is a key regulator of death receptor resistance in HRS cells.

IntroductionAlthough organic and inorganic arsenic-containing compounds are environmental toxins, they have been used for more than 100 years for the treatment of human diseases. 1,2 Salvarsan, active against syphilis, 3 or melarsoprol, still used for the treatment of African sleeping sickness, 4 are examples of organic arsenicals. Fowler solution, which was used for the treatment of chronic myeloid leukemia 5 (CML) or psoriasis, 6 is an example of inorganic arsenic. Most of these drugs have been replaced by others, as it became clear that arsenic causes diverse pathologies and increases the risk of cancer. 7,8 Since the discovery that arsenic trioxide (As 2 O 3 ) is an efficient drug for the treatment of acute promyelocytic leukemia 9 (APL), As 2 O 3 was reintroduced in current therapeutic concepts. Initial clinical studies focused on the treatment of hematopoietic malignancies. Currently, the action of arsenic on many other tumor entities is under investigation. 10,11 Depending on the cell type and the applied concentrations of arsenic, diverse cellular effects are observed (for a recent review, see Miller et al 12 ). Low concentrations can induce differentiation or cell cycle arrest, whereas high concentrations can induce apoptosis. Mechanisms leading to induction of apoptosis were extensively studied. An important role was attributed to arsenic-triggered degradation of specific proteins with prosurvival function. The strongest correlation was found with the degradation of the promyelocytic leukemia/retinoic acid receptor-␣ (PML/RAR-␣) protein in APL, 13 but also degradation of the viral Tax protein in human T-cell lymphotropic virus (HTLV)-induced T-cell leukemia has been reported. 14 However, these mechanisms cannot explain the induction of apoptosis in many other cell types. As a general finding, all 3 groups of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), p38, and Jun Nterminal kinase (JNK), are activated in response to arsenic. 15,16 This activation may be responsible for the carcinogenic effects of arsenic, but MAPK activation is not required for arsenic-induced apoptosis. 17 Furthermore, the generation of reactive oxygen species (ROS) has been implicated in arsenic-mediated apoptosis. 18 The biologic effects of arsenic may be attributed to structural and functional alterations of critical cellular proteins by its reactivity with sulfhydryl groups. 19 The resulting loss of function of specific enzymes, including kinases and phosphatases, functionally alters diverse signaling pathways. For example, arsenicmediated inhibition of MAPK phosphatases, which contain cysteines in their catalytic pocket, induces MAPK activation. 16 Arsenic exerts an opposite effect on the IB kinase (IKK) complex. 20 The IKK complex, which is composed of the 2 catalytic IKK␣ and IKK␤ subunits and the regulatory IKK␥/NEMO component, is the central mediator of nuclear factor-B (NF-B)-inducing stimuli. 21 Activation of the IKK complex results in phosphorylation of IBs, which subsequently ar...