Similarly, in a phase I/II trial, BTZ and low dose cytarabine arabinoside showed clinical response in 36% of high-risk MDS patients. These BU 4061T studies also demonstrated that BTZ is more effective when combined with other chemotherapeutic agents for treating high-risk MDS patients. Nonetheless, chemotherapy is usually associated with severe side effects that might lead to patient’s death. Most likely, targeted therapies that selectively exploit specific survival molecules are more effective and notably associated with fewer side effects. The development of targeted therapies for MDS has been particularly challenging due to the complexity of the oncogenic systems contributing to the survival of MDS cells. The MEK/ERK pathway plays key roles in controlling cell survival and cell cycle progression, and its deregulation is often implicated in developing drug resistance and cancer progression. Upregulation of p-ERK has been observed in the majority of AML cases, and elevated expression of ERK in AMLs is associated with a poor prognosis. Furthermore, introduction of a constitutively activated form of MEK into hematopoietic stem cells causes myeloid malignancies such as MDS and myeloproliferative neoplasms. Persistant activation of MEK/ERK pathway mediates drug resistance in leukemia cells. These studies suggest that MEK/ERK pathway may play a role in the development of MDS and in mediating drug resistance. In this study, we investigated the effects of BTZ in a human MDS cell line SKM-1. Our results demonstrated that p-ERK1/2 is highly expressed in SKM-1 cells. The expression of p-ERK1/2 was markedly decreased after treatment with BTZ. In contrast, treatment with BTZ resulted in upregulation of ERK in the BTZresistant cell line SKM-1R. However, the resistance to BTZ in SKM-1R cells was reversed by the MEK inhibitors U0126 and PD98059. 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. Despite the clinical success of BTZ in treating plasma cell myeloma, resistance to this drug remains a significant problem. A phase 2 study showed that the rate of response to BTZ was only 35% and patients developed resistance to BTZ 12 months after the initial treatment. A recent study showed that only 40% patients with relapsed plasma cell myeloma responded to the retreatment. Significant progress has been made in elucidating molecular mechanisms of BTZ resistance. AZ 960 Oerlemans et al found an Ala49Thr mutation residing in a highly conserved BTZ-binding pocket in the proteasome b5-subunit protein in BTZ resistant human myelomonocytic THP1 cells. The mutation resulted in overexpression of the PSMB5 protein. Upregulated expression of the PSMB5 gene was confirmed in bone marrow cells of multiple myeloma patients who developed BTZ resistance. Ria et al suggested that HIF-1a may also play a role in developing BTZ resistance by inducing angiogenesis in tumors. Relative few studies can be found in the literature regarding BTZ and AML. Most of these articles documented the effectiveness of BTZ for a subset of AML patients. BTZ resistant AML cell lines have not been established so far. However, it has been shown that persisting NF-kB activity may be responsible for the survival of CD34 AML cells after BTZ treatment. When the IKK inhibitor BMS-345541 was used in combination with BTZ, the survival of CD34 AML cells was reduced, which suggest that NF-kB may be involved in BTZ resistance in AML. Bcl-2 overexpression has been suggested as a potential mechanism of BTZ resistance in human lymphoid cells. Overexpression of heat shock proteins and T-cell factor 4 has been reported in BTZ resistant B-lymphoma cells.