Lapatinib Induces Autophagy, Apoptosis and Megakaryocytic Differentiation in Chronic Myelogenous Leukemia K562 Cells

Lapatinib is an oral, small-molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptors (EGFR, or ErbB/Her) in solid tumors. Little is known about the effect of lapatinib on leukemia. Using human chronic myelogenous leukemia (CML) K562 cells as an experimental model, we found that lapatinib simultaneously induced morphological changes resembling apoptosis, autophagy, and megakaryocytic differentiation. Lapatinib-induced apoptosis was accompanied by a decrease in mitochondrial transmembrane potential and was attenuated by the pancaspase inhibitor z-VAD-fmk, indicating a mitochondria-mediated and caspase-dependent pathway. Lapatinib-induced autophagic cell death was verified by LC3-II conversion, and upregulation of Beclin-1. Further, autophagy inhibitor 3-methyladenine as well as autophagy-related proteins Beclin-1 (ATG6), ATG7, and ATG5 shRNA knockdown rescued the cells from lapatinib-induced growth inhibition. A moderate number of lapatinib-treated K562 cells exhibited features of megakaryocytic differentiation. In summary, lapatinib inhibited viability and induced multiple cellular events including apoptosis, autophagic cell death, and megakaryocytic differentiation in human CML K562 cells. This distinct activity of lapatinib against CML cells suggests potential for lapatinib as a therapeutic agent for treatment of CML. Further validation of lapatinib activity in vivo is warranted

Risk of infection in patients with lymphoma receiving rituximab: systematic review and meta-analysis

Background: The addition of Rituximab (R) to standard chemotherapy (C) has been reported to improve the end of treatment outcome in patients affected by CD-20 positive malignant lymphomas (CD20+ ML). Nevertheless, given the profound and prolonged immunosuppression produced by R there are concerns that severe infections may arise. A systematic review and meta-analysis were performed to determine whether or not the addition of R to C may increase the risk of severe infections in adults undergoing induction therapy for CD20+ ML.Methods: Only randomised controlled trials comparing R-C to C standard alone in adult patients with CD20+ ML were included. Meta-analysis was performed on overall incidence of severe infection, risk of dying as the consequence of infection, risk of febrile neutropenia, risk of severe leucopenia, risk of severe granulocytopenia and overall response assuming a fixed effect model. Heterogeneity was investigated, if present and I-2 >20%, according to several predefined baseline characteristics of the study populations.Results: Several relevant results have emerged. First, the addition of R to standard C does not increase the overall risk of severe infections (RR = 1.00; 95% CI 0.87 to 1.14) nor does it increase the risk of dying as a consequence of infection (RR = 1.60; 95% CI 0.68 to 3.75). Second, we confirmed that the addition of R to standard C increases the proportion of overall response (RR = 1.12; 95% CI 1.09 to 1.15), but it also increases the risk of severe leucopenia (RR = 1.24; 95% CI 1.12 to 1.37) and granulocytopenia (RR = 1.07; 95% CI 1.02 to 1.12).Conclusions: R-C is superior to standard C in terms of overall response and it does not increase the overall incidence of severe infection. However, data on special groups of patients (for example, HIV positive subjects and HBV carriers) are lacking. In our opinion more studies are needed to explore the potential effect of R on silent and chronic viral infections

Increased Level of Myeloid-Derived Suppressor Cells, Programmed Death Receptor Ligand 1/Programmed Death Receptor 1, and Soluble CD25 in Sokal High Risk Chronic Myeloid Leukemia

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Genetic modification of primary human B cells to model high-grade lymphoma

Abstract: Sequencing studies of diffuse large B cell lymphoma (DLBCL) have identified hundreds of recurrently altered genes. However, it remains largely unknown whether and how these mutations may contribute to lymphomagenesis, either individually or in combination. Existing strategies to address this problem predominantly utilize cell lines, which are limited by their initial characteristics and subsequent adaptions to prolonged in vitro culture. Here, we describe a co-culture system that enables the ex vivo expansion and viral transduction of primary human germinal center B cells. Incorporation of CRISPR/Cas9 technology enables high-throughput functional interrogation of genes recurrently mutated in DLBCL. Using a backbone of BCL2 with either BCL6 or MYC, we identify co-operating genetic alterations that promote growth or even full transformation into synthetically engineered DLBCL models. The resulting tumors can be expanded and sequentially transplanted in vivo, providing a scalable platform to test putative cancer genes and to create mutation-directed, bespoke lymphoma models

Toward a New Molecular Taxonomy of Diffuse Large B-cell Lymphoma

Abstract Diffuse large B-cell lymphoma (DLBCL) represents a grouping of clinically and biologically heterogeneous tumors. Application of advanced molecular technology has significantly expanded our knowledge of DLBCL pathobiology, allowing identification of subgroups with common, potentially targetable, biological themes. Here, we review the recent molecular analyses that could provide a paradigm shift to a new taxonomy, foundational to the rational transition to precision medicine. We discuss how classification systems may be synthesized into a common taxonomy, drawing strength from the relationships between genetic alterations, gene expression, and tumor microenvironment. Finally, challenges to translating such a taxonomy to the clinic will be outlined.</jats:p