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

Atul Kumar,Bithiah Grace Jaganathan,Jina Bhattacharyya

doi:10.1038/s41598-017-10373-3

Atul Kumar, Bithiah Grace Jaganathan + Show 1 more

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https://doi.org/10.1038/s41598-017-10373-3

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Journal: Scientific Reports	Publication Date: Aug 25, 2017
Citations: 24	License type: open-access

Affiliation: Indian Institute of Technology Guwahati

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.

Highlights

Chronic myeloid leukemia (CML) is a myelo-proliferative disorder resulting in abnormally high number of myeloid cells in the bone marrow (BM)[1]
When CML (K562) cells were cultured in contact with the stromal cells in the microenvironment, CML cells were protected from the apoptotic effect of chemotherapeutic agent imatinib mesylate (IM)(Fig. 1a), as reported by others[16]
When both adherent and non-adherent fractions of CML cells were analyzed for apoptosis, we found a significantly reduced apoptosis in Imatinib mesylate (IM) treated stroma adherent CML cells compared to the control cells (Fig. 1e)

Summary

Introduction

Chronic myeloid leukemia (CML) is a myelo-proliferative disorder resulting in abnormally high number of myeloid cells in the bone marrow (BM)[1]. BCR-ABL tyrosine kinase activity is essential for tumorigenesis[3] and regulates RAS-MAPK-ERK4, 5, JNK-MAPK6, PI3K7, and STAT58, 9 signaling pathways in CML cells. These signaling pathways provide proliferative advantage to CML cells and regulate anti-apoptotic genes. Oncogene independent signaling pathways involved in stroma mediated chemoprotection of CML cells are still not clearly understood. It is still not known the importance of cell-cell interaction in chemoprotection and whether interaction with stromal cells could lead to emergence of chemoresistant CML cells at physiologically relevant dosage of IM. We sought to identify the stroma dependent aberrant molecular signaling pathways in CML cells that play a crucial role in CML chemoprotection and emergence of chemoresistance

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