A Naturally Generated Decoy of the Prostate Apoptosis Response-4 Protein Overcomes Therapy Resistance in Tumors

Primary tumors are often heterogeneous, composed of therapy-sensitive and emerging therapy-resistant cancer cells. Interestingly, treatment of therapy-sensitive tumors in heterogeneous tumor microenvironments results in apoptosis of therapy-resistant tumors. In this study, we identify a prostate apoptosis response-4 (Par-4) amino-terminal fragment (PAF) that is released by diverse therapy-sensitive cancer cells following therapy-induced caspase cleavage of the tumor suppressor Par-4 protein. PAF caused apoptosis in cancer cells resistant to therapy and inhibited tumor growth. A VASA segment of Par-4 mediated its binding and degradation by the ubiquitin ligase Fbxo45, resulting in loss of Par-4 proapoptotic function. Conversely, PAF, which contains this VASA segment, competitively bound to Fbxo45 and rescued Par-4–mediated induction of cancer cell–specific apoptosis. Collectively, our findings identify a molecular decoy naturally generated during apoptosis that inhibits a ubiquitin ligase to overcome therapy resistance in tumors

Commentary on the WHO classification of tumors of lymphoid tissues (2008): “Gray zone” lymphomas overlapping with Burkitt lymphoma or classical Hodgkin lymphoma

The 2008 WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues has introduced two new categories of high-grade B-cell lymphomas: entities in which features of diffuse large B-cell lymphoma (DLBCL) overlap with Burkitt lymphoma (DLBCL/BL) or classical Hodgkin lymphoma (DLBCL/HL). The DLBCL/BL category encompasses cases that resemble Burkitt lymphoma morphologically, but have one or more immunophenotypic or molecular genetic deviations that would exclude it from the BL category; conversely, some cases have immunophenotypic and/or genetic features of BL, but display cytologic variability unacceptable for BL. Many of the cases in the DLBCL/BL category contain a translocation of MYC as well as either BCL2 or BCL6 (so-called double-hit lymphomas) and have a very aggressive clinical behavior. The DLBCL/HL category encompasses lymphomas that exhibit the morphology of classical Hodgkin lymphoma but the immunophenotype of DLBCL, or vice versa. Most DLBCL/HL cases described present as mediastinal masses, but this category is not limited to mediastinal lymphomas. These new categories acknowledge the increasing recognition of cases that display mixed features of two well-established diseases. Whether the existence of such cases reflects shortcomings of our current diagnostic armamentarium or a true disease continuum in which such hybrid or intermediate neoplasms actually exist remains to be determined

Commentary on the WHO classification of tumors of lymphoid tissues (2008): indolent B cell lymphomas

The 4th edition of the World Health Organization classification of tumors of hematopoietic and lymphoid tissues introduces many new items to the classification scheme of the so-called indolent B cell lymphomas. New proposed entities, such as splenic B cell lymphoma/leukemia, unclassifiable, splenic diffuse red pulp small B cell lymphoma, hairy cell leukemia variant, pediatric follicular lymphoma, and pediatric marginal zone lymphoma have been coined, and some definitions of established diseases, such as chronic lymphocytic leukemia or Waldenström’s macroglobulinemia have been revised. One aspect of major importance is the recent description of small clonal B cell populations, in part with a CLL phenotype, and their relationship to B-CLL. Some new subtypes or variants of follicular lymphoma with distinct clinicopathologic and/or molecular genetic characteristics have been described, including primary follicular lymphomas of the duodenum and pediatric follicular lymphomas. Furthermore, the impact of some probably early, or precursor lesions, such as follicular lymphoma in situ is discussed. Overall, we succinctly discuss the essential elements of the revisions made in the updated classification, and we identify potential opportunities for refinement of new or provisional categories in subsequent classifications

Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2-MALT1 in MALT lymphoma.

MALT1 is the only known paracaspase and is a critical mediator of B- and T-cell receptor signalling. The function of the MALT1 gene is subverted by oncogenic chimeric fusions arising from the recurrent t(11;18)(q21;q21) aberration, which is the most frequent translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. API2-MALT1-positive MALT lymphomas manifest antibiotic resistance and aggressive clinical behaviour with poor clinical outcome. However, the mechanisms underlying API2-MALT1-induced MALT lymphomagenesis are not fully understood. Here we show that API2-MALT1 induces paracaspase-mediated cleavage of the tumour suppressor protein LIMA1. LIMA1 binding by API2-MALT1 is API2 dependent and proteolytic cleavage is dependent on MALT1 paracaspase activity. Intriguingly, API2-MALT1-mediated proteolysis generates a LIM domain-only (LMO)-containing fragment with oncogenic properties in vitro and in vivo. Importantly, primary MALT lymphomas harbouring the API2-MALT1 fusion uniquely demonstrate LIMA1 cleavage fragments. Our studies reveal a novel paracaspase-mediated oncogenic gain-of-function mechanism in the pathogenesis of MALT lymphoma.This work was supported in part by NIH grants R01 DE119249 and R01 CA136905 (K.S.J.E-J.), R01 CA140806 (M.S.L.) and the Department of Pathology at the University of Michigan.This is the accepted manuscript. The final version is available from Nature at http://www.nature.com/ncomms/2015/150108/ncomms6908/full/ncomms6908.html

KDM2A represses transcription of centromeric satellite repeats and maintains the heterochromatic state

Heterochromatin plays an essential role in the preservation of epigenetic information, the transcriptional repression of repeti- tive DNA elements and inactive genes, and the proper segregation of chromosomes during mitosis. Here we identify KDM2A, a JmjC-domain containing histone demethylase, as a heterochro- matin-associated and HP1-interacting protein that promotes HP1 localization to chromatin. We show that KDM2A is required to maintain the heterochromatic state, as determined using a candidate-based approach coupled to an in vivo epigenetic reporter system. Remarkably, a parallel and independent siRNA screen also detected a role for KDM2A in epigenetic silencing. Moreover, we demonstrate that KDM2A associates with centromeres and represses transcription of small non-coding RNAs that are encoded by the clusters of satellite repeats at the centromere. Dissecting the relationship between heterochromatin and centromeric RNA transcription is the basis of ongoing studies. We demonstrate that forced expression of these satellite RNA transcripts compromise the heterochromatic state and HP1 localization to chromatin. Finally, we show that KDM2A is required to sustain centromeric integ- rity and genomic stability, particularly during mitosis. Since the disruption of epigenetic control mechanisms contributes to cellular transformation, these results, together with the low levels of KDM2A found in prostate carcinomas, suggest a role for KDM2A in cancer development

Commentary on the WHO classification of tumors of lymphoid tissues (2008): aggressive B-cell lymphomas

In the novel WHO classification 2008, the classification of aggressive B-cell lymphoma has been revised for several categories with the aim to define “clean” entities. Within large B-cell lymphoma, a few distinct clinico-pathological entities have been recognized with more clinically defined entities than pathologically defined ones. The majority of known morphological variations were not considered to merit more than classification as a variant of DLBCL, not otherwise specified. Specifically, a biological subgrouping of DLBCL on the basis of molecular (activated B-cell versus germinal center B-cell) or immunophenotypic (CD5+) features was felt to be too immature to include at this stage. The role of EBV in aggressive B-cell lymphoma has been explored in more depth with the recognition of several novel and re-defined clinico-pathological entities. Also, in these diseases, clinical definitions play a very dominant role in the WHO classification 2008

Apoptosis of t(14;18)-positive lymphoma cells by a Bcl-2 interacting small molecule

Overexpression of Bcl-2 protein occurs via both t(14;18)-dependent and independent mechanisms and contributes to the survival and chemoresistance of non-Hodgkin lymphomas. HA14–1 is a nonpeptidic organic small molecule, which has been shown to inhibit the interaction of Bcl-2 with Bax, thereby interfering with the antiapoptotic function of Bcl-2. In this study, we sought to determine the in vitro efficacy of HA14–1 as a therapeutic agent for non-Hodgkin lymphomas expressing Bcl-2. Assessment of cell viability demonstrated that HA14–1 induced a dose- (IC50 = 10 μM) and time-dependent growth inhibition of a cell line (SudHL-4) derived from a t(14;18)-positive, Bcl-2-positive, non-Hodgkin lymphoma. HA14–1 effectively induced apoptosis via a caspase 3-mediated pathway but did not affect either the p38 MAPK or p44/42 MAPK pathways. Western blot analyses of Bcl-2 family proteins and other cell cycle-associated proteins were performed to determine the molecular sequelae of HA14–1-induced apoptosis. The results show down-regulation of Mcl-1 but up-regulation of p27kip1, Bad, Bcl-xL, and Bcl-2 proteins, without change in Bax levels during HA14–1-mediated apoptosis. Our findings further elucidate the cellular mechanisms accompanying Bcl-2 inhibition and demonstrate the potential of Bcl-2 inhibitors as therapeutic agents for the treatment of non-Hodgkin lymphomas

International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease.

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)-associated MCD, POEMS-associated MCD, and HHV-8-/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients

Correction. "The 5th edition of The World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms" Leukemia. 2022 Jul;36(7):1720-1748

We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms