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A patient with a long history of celiac sprue developed a pleomorphic intestinal lymphoma. Cell suspensions of tumor cells and immunoperoxidase labeling of cell surface antigens in frozen tissue sections clearly showed the lymphoma to be of T-cell origin, despite the presence of other nontumor cells bearing enzyme markers of histiocytes. These findings may have important implications on the cellular origin of lymphomas developing in patients with celiac sprue. [ABSTRACT FROM AUTHOR]

In this article the authors comment on the study by Fedele and colleagues on the expansion of cytotoxic T lymphocyte (CTL) in allogeneic hematopoietic stem cell transplant recipients. The authors predict that the platelet-derived growth factor receptor (PDGFR) and receptor tyrosine kinases (RTKs) may play a role in large granular lymphocyte (LGL) leukemia patients. However, there is an expansion of LGLs in chronic myeloid leukemia (CML) patients which are treated wtih RTK inhibitors.

Key Clinical Message In this report, a case of relapsed Ph+ ALL was remedied by reinduction, and consolidation regimen of TKI and Flu+ Ara-C+ IDA ( FLAI) combination, followed by haploidentical SCT. Results suggest that FLAI together with TKI and subsequently with haploidentical SCT could be applied for relapsed Ph+ ALL. [ABSTRACT FROM AUTHOR]

Abstract: We developed a strategy that can prolong in vitro growth of T cell type of large granular lymphocyte (T-LGL) leukemia cells. Primary CD8+ lymphocytes from T-LGL leukemia patients were stably transduced with the retroviral tax gene derived from human T cell leukemia virus type 2. Expression of Tax overrode replicative senescence and promoted clonal expansion of the leukemic CD8+ T cells. These cells exhibit features characteristic of leukemic LGL, including resistance to FasL-mediated apoptosis, sensitivity to the inhibitors of sphingosine-1-phosphate receptor and IκB kinases as well as expression of cytotoxic gene products such as granzyme B, perforin and IFNγ. Collectively, these results indicate that this leukemia cell model can duplicate the main phenotype and pathophysiological characteristics of the clinical isolates of T-LGL leukemia. This model should be useful for investigating molecular pathogenesis of the disease and for developing new therapeutics targeting T-LGL leukemia. [Copyright &y& Elsevier]

The blood cancer T cell large granular lymphocyte (T-LGL) leukemia is a chronic disease characterized by a clonal proliferation of cytotoxic T cells. As no curative therapy is yet known for this disease, identification of potential therapeutic targets is of immense importance. In this paper, we perform a comprehensive dynamical and structural analysis of a network model of this disease. By employing a network reduction technique, we identify the stationary states (fixed points) of the system, representing normal and diseased (T-LGL) behavior, and analyze their precursor states (basins of attraction) using an asynchronous Boolean dynamic framework. This analysis identifies the T-LGL states of 54 components of the network, out of which 36 (67%) are corroborated by previous experimental evidence and the rest are novel predictions. We further test and validate one of these newly identified states experimentally. Specifically, we verify the prediction that the node SMAD is over-active in leukemic T-LGL by demonstrating the predominant phosphorylation of the SMAD family members Smad2 and Smad3. Our systematic perturbation analysis using dynamical and structural methods leads to the identification of 19 potential therapeutic targets, 68% of which are corroborated by experimental evidence. The novel therapeutic targets provide valuable guidance for wet-bench experiments. In addition, we successfully identify two new candidates for engineering long-lived T cells necessary for the delivery of virus and cancer vaccines. Overall, this study provides a bird's-eye-view of the avenues available for identification of therapeutic targets for similar diseases through perturbation of the underlying signal transduction network. [ABSTRACT FROM AUTHOR]