The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

Key Points• DLBCL patients with MYC/BCL2 coexpression demonstrate inferior prognosis and high-risk gene expression signatures.Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)-like and unfavorable activated B-cell (ABC)-like subtypes based on gene expression signatures. In this study, we analyzed 893 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We show that MYC/BCL2 protein coexpression occurred significantly more commonly in the ABC subtype. Patients with the ABC or GCB subtype of DLBCL had similar prognoses with MYC/BCL2 coexpression and without MYC/BCL2 coexpression. Consistent with the notion that the prognostic difference between the 2 subtypes is attributable to MYC/BCL2 coexpression, there is no difference in gene expression signatures between the 2 subtypes in the absence of MYC/BCL2 coexpression. DLBCL with MYC/BCL2 coexpression demonstrated a signature of marked downregulation of genes encoding extracellular matrix proteins, those involving matrix deposition/remodeling and cell adhesion, and upregulation of proliferation-associated genes. We conclude that MYC/BCL2 coexpression in DLBCL is associated with an aggressive clinical course, is more common in the ABC subtype, and contributes to the overall inferior prognosis of patients with ABC-DLBCL. In conclusion, the data suggest that MYC/BCL2 coexpression, rather than cell-of-origin classification, is a better predictor of prognosis in patients with DLBCL treated with R-CHOP. (Blood. 2013;121(20):4021-4031)

Immune homeostasis is essential for the normal functioning of the immune system, and its breakdown leads to fatal inflammatory diseases. We report here the identification of a member of the tumor necrosis factor-alpha-induced protein-8 (TNFAIP8) family, designated TIPE2, that is required for maintaining immune homeostasis. TIPE2 is preferentially expressed in lymphoid tissues, and its deletion in mice leads to multiorgan inflammation, splenomegaly, and premature death. TIPE2-deficient animals are hypersensitive to septic shock, and TIPE2-deficient cells are hyper-responsive to Toll-like receptor (TLR) and T cell receptor (TCR) activation. Importantly, TIPE2 binds to caspase-8 and inhibits activating protein-1 and nuclear factor-kappaB activation while promoting Fas-induced apoptosis. Inhibiting caspase-8 significantly blocks the hyper-responsiveness of TIPE2-deficient cells. These results establish that TIPE2 is an essential negative regulator of TLR and TCR function, and its selective expression in the immune system prevents hyperresponsiveness and maintains immune homeostasis.

The pivotal discovery that the death proteases caspase 8 (FLICE) and caspase 10 (Mch4/FLICE2) are recruited to the CD-95 and tumor necrosis factor receptor-1 signaling complexes suggested a mechanism used by these cytotoxic receptors to initiate apoptosis. In this report, we describe the cloning and characterization of I-FLICE, a novel inhibitor of tumor necrosis factor receptor-1-and CD-95-induced apoptosis. The overall architecture of I-FLICE is strikingly similar to that of FLICE and Mch4/FLICE2. However, I-FLICE lacks both a catalytic active site and residues that form the substrate binding pocket, in keeping with its dominant negative inhibitory function. I-FLICE is the first example of a catalytically inert caspase that can inhibit apoptosis.The cell death machinery is conserved throughout evolution and is composed of activators, inhibitors, and effectors (1). The effector arm of the cell death pathway is composed of a rapidly growing family of cysteine aspartate-specific proteases termed caspases (2). As implied by the name, these cysteine proteases cleave substrates following an aspartate residue (2, 3). Caspases are normally present as single polypeptide zymogens and contain an N-terminal prodomain and large and small catalytic subunits (4 -6). The two-chain active enzyme (composed of the large and small subunits) is obtained following proteolytic processing at internal Asp residues (4 -6). As such, caspases are capable of activating each other in a manner analogous to zymogen activation that is observed in the coagulation cascade (7). The identification of FLICE and Mch4/ FLICE2 as receptor-associated caspases suggested a surprisingly direct mechanism for activation of the death pathway by the cytotoxic receptors CD-95 and TNFR-1 1 (7-10). Upon activation, both receptors use their death domains to bind the corresponding domain in the adaptor molecule FADD (Fasassociated death domain protein) (8 -10). Dominant negative versions of FADD that lack the N-terminal segment but still retain the death domain potently inhibit both CD-95-and TNFR-1-induced apoptosis (11,12). Given the importance of the N-terminal segment in engaging the death pathway, it has been termed the death effector domain (DED) (11).Remarkably, the DED is present within the prodomain of FLICE and Mch4/FLICE2, and mutagenesis studies suggest that a homophilic interaction between the DED of FADD and the corresponding domain in FLICE or Mch4/FLICE2 is responsible for the recruitment of these proteases to the CD-95 and TNFR-1 signaling complexes (8 -11). Taken together, these data are consistent with FLICE and Mch4/FLICE2 being apical enzymes that initiate precipitous proteolytic processing of downstream caspases resulting in apoptosis (7,(13)(14)(15). A number of viral gene products antagonize CD-95-and TNFR-1-mediated killing as a means to persist in the infected host (16). The poxvirus-encoded serpin CrmA and baculovirus gene product p35 are direct caspase inhibitors (3). In contrast, the molluscum contagiosum virus protein MC159 and the e...

Molluscum contagiosum virus proteins MC159 and MC160 and the equine herpesvirus 2 protein E8 share substantial homology to the death effector domain present in the adaptor molecule Fas-associated death domain protein (FADD) and the initiating death protease FADD-like interleukin-1␤-converting enzyme (FLICE) (caspase-8). FADD and FLICE participate in generatingthe death signal from both tumor necrosis factor receptor-1 (TNFR-1) and the CD-95 receptor. The flow of death signals from TNFR-1 occurs through the adaptor molecule tumor necrosis factor receptor-associated death domain protein (TRADD) to FADD to FLICE, whereas for CD-95 the receptor directly communicates with FADD and then FLICE. MC159 and E8 inhibited both TNFR-1-and CD-95-induced apoptosis as well as killing mediated by overexpression of the downstream adaptors TRADD and FADD. Neither viral molecule, however, inhibited FLICE-induced killing, consistent with an inhibitory action upstream of the active death protease. These data suggest the existence of a novel strategy employed by viruses to attenuate host immune killing mechanisms. Given that bovine herpesvirus 4 protein E1.1 and Kaposi's sarcoma associated-herpesvirus protein K13 also possess significant homology to the viral inhibitory molecules MC159, MC160, and E8, it may be that this class of proteins is used ubiquitously by viruses to evade host defense.Cell suicide is a defense mechanism employed by host cells to inhibit viral replication and persistence. As a consequence, viruses have evolved numerous strategies to attenuate apoptosis (1). For example, the Epstein-Barr virus (EBV) encodes BHRF1, a homolog of the mammalian anti-apoptosis molecule bcl-2, and the cowpox virus encodes a serpin-like protein, CrmA, that blocks apoptosis by inhibiting proteases belonging to the caspase family.Molluscum contagiosum virus (MCV) is the only poxvirus family member still associated with human disease (2). It usually causes asymptomatic cutaneous neoplasms that can spontaneously regress. However, with the advent of immunocompromised populations, particularly those afflicted with acquired immunodeficiency syndrome, MCV infection has become a clinical challenge (3). Unfortunately, due to the inability to grow the virus in tissue culture cells and the lack of a suitable animal model, little is known about host-virus relationships (4). Equine herpesvirus 2 (EHV2) is a member of the ␥-herpesvirus subfamily that also includes herpesvirus saimiri, EBV, Kaposi's sarcoma-associated herpesvirus (KSHV), and bovine herpesvirus 4 (5, 6). Although EHV2 is ubiquitously distributed and has been implicated as a pathogen in immunosuppressed states, its mode of evading the host immune response is uncertain. However, the recent availability of the MCV and EHV2 genome sequences has begun to identify genes that suggest potential pathogenic mechanisms (7,8).MCV, surprisingly, does not encode many of the immunoregulatory molecules present in other poxviruses, especially those that antagonize the host cytokine-mediated inflammatory...