Hodgkin lymphoma (HL) is composed of two distinct pathological entities, nodular lymphocyte predominant HL and classic HL, the latter with four subtypes. In contrast with most other human lymphomas, ...in which the neoplastic cells are a major population of the tumour constituents, the neoplastic ‘Hodgkin (H) and Reed–Sternberg (RS)’ cells usually account for less than 10% of tumour bulk against an inflammatory background. The neoplastic cells of HL are of B-cell lineage (PAX5+) in virtually all cases. HL usually affects young patients with a localised nodal disease and its clinical behaviour is typically indolent. Patients respond well to chemotherapy with cure rates of 80–90% and the recent finding of PD-L1 expression, an immune checkpoint, warrants the use of immunotherapy for some patients with recurrent and/or refractory HL.
The enigmatic RS cells of HL are unique in their abundant cytoplasm and characteristic bilobed nuclei with eosinophilic prominent nucleoli, imparting an ‘owl-eye’ appearance. H cells are mononuclear variants. The viral inclusion-like morphology was a clue on the way to discovering an association between classic HL and Epstein–Barr virus (EBV). However, this association is variable in different geographic regions and in pathological subtypes, and correlates with older age (>60 years) and socioeconomic status, indicating that environmental factors are likely involved in HL pathogenesis. Virus-associated endoplasmic reticulum (ER) stress also may contribute to mechanisms underlying the characteristic morphological features of HRS cells. ER stress has been found to induce aberrant, cytoplasmic cyclin A expression, leading to nuclear hyperdiploidy. Aberrant expression of cyclin A is commonly associated with HRS cell morphology in HL, probably through EBV-latent membrane protein-1 (LMP1) signalling. Shelterin also may play a role in the morphogenesis of multinucleated RS cells. In addition, EBV-positive and -negative HL cases express survival, but not death signals of ER stress at similar levels and EBV-LMP1 transfection increases expression of survival signals in HL cell lines. These data suggest that surviving ER stress may be involved in HL pathogenesis.
Peripheral T cell lymphomas (PTCLs) are a heterogeneous and poorly understood group of non-Hodgkin lymphomas. Here we combined whole-exome sequencing of 12 tumor-normal DNA pairs, RNA sequencing ...analysis and targeted deep sequencing to identify new genetic alterations in PTCL transformation. These analyses identified highly recurrent epigenetic factor mutations in TET2, DNMT3A and IDH2 as well as a new highly prevalent RHOA mutation encoding a p.Gly17Val alteration present in 22 of 35 (67%) angioimmunoblastic T cell lymphoma (AITL) samples and in 8 of 44 (18%) PTCL, not otherwise specified (PTCL-NOS) samples. Mechanistically, the RHOA Gly17Val protein interferes with RHOA signaling in biochemical and cellular assays, an effect potentially mediated by the sequestration of activated guanine-exchange factor (GEF) proteins. In addition, we describe new and recurrent, albeit less frequent, genetic defects including mutations in FYN, ATM, B2M and CD58 implicating SRC signaling, impaired DNA damage response and escape from immune surveillance mechanisms in the pathogenesis of PTCL.
There is a demand to understand B-cell lymphoma pathogenesis better, to identify new markers, and to define multiple lymphoproliferative disorders more accurately. MicroRNAs (miRNAs) are regulators ...of protein translation, comprising a group of more than 1500 short noncoding single-strand RNA molecules of approximately 22 nucleotides in length. They are easily detectable in fresh or paraffin-embedded diagnostic tissue and serum. Expression of individual miRNAs and miRNA signatures allows specific cell-differentiation stages to be identified, and is a powerful diagnostic and prognostic method. Here we review what is known about the pathogenic relevance of miRNAs, and use of miRNAs for the diagnosis and prognosis of B-cell lymphomas. Most of the published data concern chronic lymphocytic lymphoma and diffuse large B-cell lymphoma, and implicate miRNAs in the pathogenesis of these diseases. They identify miRNAs that could be used for diagnosis, prognosis, or prediction of response to specific therapies.
Splenic Marginal Zone Lymphoma Piris, Miguel A., Dr; Onaindía, Arantza; Mollejo, Manuela
Best practice & research. Clinical haematology,
03/2017, Letnik:
30, Številka:
1-2
Journal Article
Recenzirano
Abstract Splenic marginal zone lymphoma (SMZL) is an indolent small B-cell lymphoma involving the spleen and bone marrow characterized by a micronodular tumoral infiltration that replaces the ...preexisting lymphoid follicles and shows marginal zone differentiation as a distinctive finding. SMZL cases are characterized by prominent splenomegaly and bone marrow and peripheral blood infiltration. Cells in peripheral blood show a villous cytology. Bone marrow and peripheral blood characteristic features usually allow a diagnosis of SMZL to be performed. Mutational spectrum of SMZL identifies specific findings, such as 7q loss and NOTCH2 and KLF2 mutations, both genes related with marginal zone differentiation. There is a striking clinical variability in SMZL cases, dependent of the tumoral load and performance status. Specific molecular markers such as 7q loss, p53 loss/mutation, NOTCH2 and KLF2 mutations have been found to be associated with the clinical variability. Distinction from Monoclonal B-cell lymphocytosis with marginal zone phenotype is still an open issue that requires identification of precise and specific thresholds with clinical meaning.
Vorinostat (suberoylanilide hydroxamic acid, SAHA), an inhibitor of class I and II histone deacetylases, has been approved for the treatment of cutaneous T-cell lymphoma. In spite of emerging ...information on the effect of vorinostat in many types of cancer, little is yet known about this drug's mechanism of action, which is essential for its proper use in combination therapy. We investigated alterations in gene expression profile over time in cutaneous T-cell lymphoma cells treated with vorinostat. Subsequently, we evaluated inhibitors of PI3K, PIM and HSP90 as potential combination agents in the treatment of cutaneous T-cell lymphoma.
The genes significantly up- or down-regulated by vorinostat over different time periods (2-fold change, false discovery rate corrected P value<0.05) were selected using the short-time series expression miner. Cell viability was assessed in vitro in cutaneous T-cell lymphoma cells through measuring intracellular ATP content. Drug interactions were analyzed by the combination index method with CalcuSyn software.
The functional analysis suggests that vorinostat modifies signaling of T-cell receptor, MAPK, and JAK-STAT pathways. The phosphorylation studies of ZAP70 (Tyr319, Tyr493) and its downstream target AKT (Ser473) revealed that vorinostat inhibits phosphorylation of these kinases. With regards to effects on cutaneous T-cell lymphoma cells, combining vorinostat with PI3K inhibitors resulted in synergy while cytotoxic antagonism was observed when vorinostat was combined with HSP90 inhibitor.
These results demonstrate the potential targets of vorinostat, underlining the importance of T-cell receptor signaling inhibition following vorinostat treatment. Additionally, we showed that combination therapies involving histone deacetylase inhibitors and inhibitors of PI3K are potentially efficacious for the treatment of cutaneous T-cell lymphoma.
Mature T cell cancers are typically aggressive, treatment resistant and associated with poor prognosis. Clinical application of immunotherapeutic approaches has been limited by a lack of target ...antigens that discriminate malignant from healthy (normal) T cells. Unlike B cell depletion, pan-T cell aplasia is prohibitively toxic. We report a new targeting strategy based on the mutually exclusive expression of T cell receptor β-chain constant domains 1 and 2 (TRBC1 and TRBC2). We identify an antibody with unique TRBC1 specificity and use it to demonstrate that normal and virus-specific T cell populations contain both TRBC1
and TRBC2
compartments, whereas malignancies are restricted to only one. As proof of concept for anti-TRBC immunotherapy, we developed anti-TRBC1 chimeric antigen receptor (CAR) T cells, which recognized and killed normal and malignant TRBC1
, but not TRBC2
, T cells in vitro and in a disseminated mouse model of leukemia. Unlike nonselective approaches targeting the entire T cell population, TRBC-targeted immunotherapy could eradicate a T cell malignancy while preserving sufficient normal T cells to maintain cellular immunity.
Primary cutaneous CD30-positive T-cell lymphoproliferative disorders are the second most common subgroup of cutaneous T-cell lymphomas. They include two clinically different entities with some ...overlapping features and borderline cases: lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. Molecular studies of primary cutaneous anaplastic large cell lymphoma reveal an increasing level of heterogeneity that is associated with histological and immunophenotypic features of the cases and their response to specific therapies. Here, we review the most significant genetic, epigenetic and molecular alterations described to date in primary cutaneous CD30-positive T-cell lymphoproliferative disorders, and their potential as therapeutic targets.
Tumour-associated macrophages (TAMs) have been associated with survival in classic Hodgkin lymphoma (cHL) and other lymphoma types. The maturation and differentiation of tissue macrophages depends ...upon interactions between colony-stimulating factor 1 receptor (CSF1R) and its ligands. There remains, however, a lack of consistent information on CSF1R expression in TAMs. A new monoclonal antibody, FER216, was generated to investigate CSF1R protein distribution in formalin fixed tissue samples from 24 reactive lymphoid tissues and 187 different lymphoma types. We also analysed the distribution of CSF1R+, CD68+ and CD163+ macrophages by double immunostaining, and studied the relationship between CSF1R expression and survival in an independent series of 249 cHL patients. CSF1R+ TAMs were less frequent in B-cell lymphocytic leukaemia and lymphoblastic B-cell lymphoma than in diffuse large B-cell lymphoma, peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma and cHL. HRS cells in cHL and, with the exception of three cases of anaplastic large cell lymphoma, the neoplastic cells in NHLs, lacked detectable CSF1R protein. A CSF1R+ enriched microenvironment in cHL was associated with shorter survival in an independent series of 249 cHL patients. CSF1R pathway activation was evident in the cHL and inactivation of this pathway could be a potential therapeutic target in cHL cases.
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