Abstract
The myelodysplastic syndromes (MDS) comprise a heterogeneous group of malignant neoplasms with distinctive clinicopathological features. Currently, there is no specific approach for the treatment of MDS. Here, we report that bortezomib (BTZ), a proteasome inhibitor that has been used to treat plasma cell myeloma, induced G2/M phase cycle arrest in the MDS cell line SKM-1 through upregulation of Wee1, a negative regulator of G2/M phase transition. Treatment by BTZ led to reduced SKM-1 cell viability as well as increased apoptosis and autophagy. The BTZ-induced cell death was associated with reduced expression of p-ERK. To elucidate the implications of downregulation of p-ERK, we established the BTZ resistant cell line SKM-1R. Our data show that resistance to BTZ-induced apoptosis could be reversed by the MEK inhibitors U0126 or PD98059. Our results suggest that MAPK pathway may play an important role in mediating BTZ resistance.
Highlights
The myelodysplastic syndromes (MDS) are a group of clonal disorders characterized by ineffective hematopoietic cell production and variable risk of transformation to acute myeloid leukemia (AML)
A recent study showed that only 40% patients with relapsed plasma cell myeloma responded to the retreatment [3]
Upregulated expression of the proteasome b5-subunit (PSMB5) gene was confirmed in bone marrow cells of multiple myeloma patients who developed BTZ resistance [24]
Summary
The myelodysplastic syndromes (MDS) are a group of clonal disorders characterized by ineffective hematopoietic cell production and variable risk of transformation to acute myeloid leukemia (AML). In a phase I/II trial, BTZ and low dose cytarabine arabinoside showed clinical response in 36% of high-risk MDS patients [7]. These studies demonstrated that BTZ is more effective when combined with other chemotherapeutic agents for treating high-risk MDS patients [5] [7]. Persistant activation of MEK/ERK pathway mediates drug resistance in leukemia cells [12,13,14,15] These studies suggest that MEK/ERK pathway may play a role in the development of MDS and in mediating drug resistance. This study provides the first evidence that MEK/ERK pathway mediates BTZ resistance and suggests that MEK/ERK inhibitors could be successfully used in conjunction with BTZ to overcome drug resistance in MDS
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