Glioblastoma Models Reveal the Connection between Adult Glial Progenitors and the Proneural Phenotype

Tumor heterogeneity is a major obstacle for finding effective treatment of Glioblastoma (GBM). Based on global expression analysis, GBM can be classified into distinct subtypes: Proneural, Neural, Classical and Mesenchymal. The signatures of these different tumor subtypes may reflect the phenotypes of cells giving rise to them. However, the experimental evidence connecting any specific subtype of GBM to particular cells of origin is lacking. In addition, it is unclear how different genetic alterations interact with cells of origin in determining tumor heterogeneity. This issue cannot be addressed by studying end-stage human tumors.To address this issue, we used retroviruses to deliver transforming genetic lesions to glial progenitors in adult mouse brain. We compared the resulting tumors to human GBM. We found that different initiating genetic lesions gave rise to tumors with different growth rates. However all mouse tumors closely resembled the human Proneural GBM. Comparative analysis of these mouse tumors allowed us to identify a set of genes whose expression in humans with Proneural GBM correlates with survival.This study offers insights into the relationship between adult glial progenitors and Proneural GBM, and allows us to identify molecular alterations that lead to more aggressive tumor growth. In addition, we present a new preclinical model that can be used to test treatments directed at a specific type of GBM in future studies

Cytogenetic analysis of adult T-Cell leukemia/ lymphoma: evaluation of a Caribbean cohort

Adult T-cell leukemia/lymphoma (ATLL) is a rare and highly aggressive type of peripheral T-cell lymphoma associated with human T-lymphotropic virus, type I (HTLV-I) infection. ATLL has a long latency and only a small percentage of HTLV-I infected individuals develop ATLL, suggesting the requirement of additional genetic events for neoplastic transformation of HTLV-I infected lymphocytes. The disease is endemic in several regions of the world, in particular, southwestern Japan and the Caribbean basin. The clinical features of Caribbean ATLL have been reported to differ from Japanese cases, includ- ing a younger age at diagnosis, higher frequency of the lymphomatous subtype, and a more aggressive clinical course [1–7]. A number of publications have described the cytogenetic profile of Japanese ATLL [8–11]; however, cytogenetic data on Caribbean ATLL are limited [5,6]. In this study, we assessed the cytogenetic alterations in a large series of Caribbean ATLL cases to investigate whether the differences in the types and frequencies of karyotype abnormalities account for the reported differ- ences in clinical presentation and outcome between Japanese and Caribbean patients

Indolent T- and NK-Cell Lymphoproliferative Disorders of the Gastrointestinal Tract: Current Understanding and Outstanding Questions

Indolent T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract are uncommon clonal neoplasms that have a protracted clinical course and limited response to therapy. In recent years, advances in the immunophenotypic, genetic, and clinical characterization of these disorders have led to increased awareness and a better understanding of disease pathogenesis. However, many questions remain unanswered, including those concerning the cell(s) of origin, inciting immune or environmental factors, and the molecular pathways underlying disease progression and transformation. In this review, we discuss recent findings regarding the immunophenotypic and genomic spectrum of these lymphoproliferative disorders and highlight unresolved issues

Targeting CD38 with Daratumumab Plus Chemotherapy for Patients with Advanced-Stage Plasmablastoid Large B-Cell Lymphoma

Plasmablastic lymphoma (PBL) is a rare and aggressive form of large B-cell lymphoma (LBCL) most commonly seen in the setting of chronic immunosuppression or autoimmune disease. The prognosis is poor and CHOP-like regimens often fail to produce durable remission; therefore, there is no established standard of care treatment. However, PBL demonstrates substantial morphologic and immunophenotypic overlap with multiple myeloma (MM), suggesting that MM therapeutics might prove useful in treating PBL. We studied the effects of treatment using the first-in-class monoclonal antibody directed against CD38, daratumumab, in combination with chemotherapy in seven patients with advanced-stage LBCL with plasmablastic features. Treatment was safe and well-tolerated. Among six evaluable patients, six patients had complete response after treatment, and four patients who met strict WHO criteria for PBL had durable response (12–31 months and ongoing)

Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract.

Indolent T-cell lymphoproliferative disorders of the gastrointestinal tract are rare clonal T-cell diseases that more commonly occur in the intestines and have a protracted clinical course. Different immunophenotypic subsets have been described, but the molecular pathogenesis and cell of origin of these lymphocytic proliferations is poorly understood. Hence, we performed targeted next-generation sequencing and comprehensive immunophenotypic analysis of ten indolent T-cell lymphoproliferative disorders of the gastrointestinal tract, which comprised CD