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Adhesion to stromal cells mediates imatinib resistance in chronic myeloid leukemia through ERK and BMP signaling pathways.

ABSTRACT: Chronic myeloid leukemia (CML) is characterized by abnormal proliferation of myeloid cells which when untreated leads to bone marrow failure. Imatinib mesylate (IM) is the first line of therapy for treatment of CML and results in remission in most cases. However, a significant percentage of patients develop chemoresistance to IM, which might be due to the presence of chemoresistant cells in the bone marrow. In the current study, we explored the role of cell-cell interaction of CML cells with the bone marrow stromal cells in the development of chemoresistance in CML. We found that the stromal cells offered long-term chemoprotection to the CML cells from the apoptotic effect of IM. These stroma interacting CML cells were maintained in a non-proliferative stage and had increased ERK1/2 and SMAD1/8 phosphorylation levels. Prolonged interaction of CML cells with the stromal cells in the presence of IM resulted in the acquisition of stroma-free chemoresistance to IM treatment. However, inhibition of actin cytoskeleton, ERK1/2 and SMAD signaling abrogated the chemoresistance acquisition and sensitized the chemoresistant CML cells to IM induced apoptosis.

SUBMITTER: Kumar A

PROVIDER: S-EPMC5572702 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Adhesion to stromal cells mediates imatinib resistance in chronic myeloid leukemia through ERK and BMP signaling pathways.

Kumar Atul A Bhattacharyya Jina J Jaganathan Bithiah Grace BG

Scientific reports 20170825 1

Chronic myeloid leukemia (CML) is characterized by abnormal proliferation of myeloid cells which when untreated leads to bone marrow failure. Imatinib mesylate (IM) is the first line of therapy for treatment of CML and results in remission in most cases. However, a significant percentage of patients develop chemoresistance to IM, which might be due to the presence of chemoresistant cells in the bone marrow. In the current study, we explored the role of cell-cell interaction of CML cells with the ...[more]

PMID: 28842696

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Project description:BackgroundType 2 diabetes mellitus has become one of the most important public health concerns worldwide. Due to its high prevalence and morbidity, there is an avid necessity to find new therapies that slow the progression and promote the regression of the disease. Imatinib mesylate is a tyrosine kinase inhibitor that binds to the Abelson tyrosine kinase and related proteins. It enhances β-cell survival in response to toxins and pro-inflammatory cytokine. The aim of this study is to evaluate the effect of imatinib on fasting plasma glucose in subjects with normal fasting glucose, subjects with impaired fasting glucose and in subjects with type 2 diabetes mellitus.MethodsWe identified 284 subjects diagnosed with chronic myeloid leukemia or gastrointestinal stromal tumors from the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran database. 106/284 subjects were treated with imatinib. We compared the effect of imatinib on fasting plasma glucose after 1 and 6 months of treatment. We used ANOVA test of repeated samples to determine statistical significance in fasting plasma glucose before imatinib treatment and the follow-up. Statistical analysis was performed with Statistical Package for the Social Sciences v22.ResultsWe included a total of 106 subjects: 76 with fasting plasma glucose concentrations < 100 mg/dL (normal FG), 19 subjects with fasting plasma glucose concentrations ≥100 mg/dL (impaired fasting glucose), and 11 subjects with ≥126 mg/dL (type 2 diabetes mellitus). We found a significant increase in fasting plasma glucose concentration in the normal fasting glucose group (p = 0.048), and a significant decrease in fasting plasma glucose concentration in the type 2 diabetes mellitus group (p = 0.042). In the impaired fasting glucose group, we also found a tendency towards a decrease in fasting plasma glucose (p = 0.076). We identified 11 subjects with type 2 diabetes mellitus, of whom, 7 (64%) had a reduction in their fasting plasma glucose concentrations after 6 months. A significant glycosylated hemoglobin reduction (p = 0.04) was observed.ConclusionSubjects with chronic myeloid leukemia or gastrointestinal stromal tumor with type 2 diabetes mellitus had a significant reduction in fasting plasma glucose and glycosylated hemoglobin at 1 and 6 months while using imatinib.

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Adhesion to stromal cells mediates imatinib resistance in chronic myeloid leukemia through ERK and BMP signaling pathways.

Publications

Adhesion to stromal cells mediates imatinib resistance in chronic myeloid leukemia through ERK and BMP signaling pathways.

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