Azithromycin (AZM) is widely used for respiratory tract infections and otitis media because of its activity against
T315I mutation of the ABL-kinase domain in chronic myeloid leukemia (CML) confers resistance to imatinib (IM) as well as second-generation tyrosine kinase inhibitors (TKIs). We report a chronic-phase CML patient undergoing IM treatment, who showed the overt existence of the T315I mutation after 15 months. We retrospectively analyzed the distribution of the T315I mutation using the invader assay and direct DNA sequencing among FACSAria-sorted populations from bone marrow cells: total mononuclear cells (TMC), hematopoietic stem cells (HSC)/Thy-1(+), HSC/Thy-1⁻, common myeloid progenitors (CMP), granulocyte macrophage progenitors (GMP), and megakaryocyte erythroid progenitors (MEP), at 0, 3, 6, 9, and 12 months after IM treatment. T315I was barely detectable by 12 months in TMC, but detectable in 19.2% of HSC/Thy-1⁻ and 46.4% of MEP at diagnosis, and finally expanded into all populations. These results suggest that the monitoring of gene mutations in HSC and progenitors at diagnosis might be helpful for the early detection of TKI-resistant CML patients and facilitate appropriate therapeutic decision.
The BCR-ABL1 fusion gene is the molecular marker of chronic myeloid leukemia (CML). The e19a2 transcript is a rare variant associated with various clinical presentations and courses of CML. We herein present a case of e19a2-positive CML who was intolerant to initial treatment with imatinib and successfully responded to subsequent nilotinib therapy. She achieved a major molecular response and has since be able to sustain it. According to the literature, achieved molecular response by imatinib monotherapy has not yet been reported in e19a2-positive CML patients. Second generation tyrosine kinase inhibitors may therefore be a more effective treatment for e19a2-positive CML patients.
3616 Mantle cell lymphoma (MCL) is an aggressive tumor and is characterized by deregulated growth and resistance to apoptosis. Reactive oxygen species (ROS) are important signal transduction molecules in regulation of cell growth, differentiation and apoptosis. Some of the ROS-generating NADPH oxidase (Nox) family enzymes are involved in neoplastic proliferation. We hypothesized that Nox-mediated generation of intracellular ROS conferred antiapoptotic activity and thus a growth advantage to MCL cells. (1) To investigate whether Nox gene expression might be specific, this study measured the expression levels of Nox genes 1–5 and dual oxidase 1 and 2 in two MCL cell lines (SP49 and SP53) and peripheral blood leukemic cells from a patient with MCL by quantitative, real-time RT-PCR. (2) Effects of antioxidants or small inhibitory RNA (siRNA) on viability of MCL cells were examined by Calcein or MTT assay. (3) Generation of intracellular ROS were measured by FACS analysis after cells were labeled by dichlorofluorescin (DCF). (4) Apoptosis was evaluated by Annexin V assay. (5) Signal transduction was estimated by Western immunoblots. MCL cell viability decreased in dose-dependent manner when cells were exposed to a dietary antioxidant, an inhibitor of flavoprotein-dependent oxidase, diphenylene iodonium (DPI) and vitamin E. RT–PCR analysis revealed that high level Nox2 mRNA expression was observed in all MCL cells, whereas little or no Nox1, Nox3-5 and Duox1-2 mRNAs was detected. Moreover, Nox2 expression in CD19+ leukemic MCL cells was significantly higher than normal CD19+ B cells (5.1-fold). SiRNA knockdown of Nox2 in these cell lines results in 27% reduction in intracellular ROS as measured by a fluorescent DCF assay, and 22% reduction in cell viability. SiNox2-RNAs inhibited superoxide production in MCL cells, and depletion of ROS by DPI or siNox2-RNAs induced apoptosis (28% or 11%, respectively). DPI treatment and siNox4RNA transfection blocked activation of the cell survival kinase AKT by attenuating phosphorylation of AKT. AKT phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) was reduced by DPI and siNox2-RNAs. Collectively, these findings suggest that ROS generated by Nox2, at least in part, transmits cell survival signals through the AKT- ASK1 pathway in MCL cells and their depletion leads to apoptosis. Disclosures: No relevant conflicts of interest to declare.
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