Abstract
Multiple myeloma with clonal plasma expansion in bone marrow is the second most common hematologic malignancy in the world. Though the improvement of outcomes from the achievement of novel agents in recent decades, the disease progresses and leads to death eventually due to the elusive nature of myeloma cells and resistance mechanisms to therapeutic agents. In addition to the molecular and genetic basis of resistance pathomechanisms, the bone marrow microenvironment also contributes to disease progression and confers drug resistance in myeloma cells. In this review, we focus on the current state of the literature in terms of critical bone marrow microenvironment components, including soluble factors, cell adhesion mechanisms, and other cellular components. Transcriptional factor nuclear factor erythroid-derived-2-like 2 (NRF2), a central regulator for anti-oxidative stresses and detoxification, is implicated in chemoresistance in several cancers. The functional roles of NRF2 in myeloid-derived suppressor cells and multiple myeloma cells, and the potential of targeting NRF2 for overcoming microenvironment-mediated drug resistance in multiple myeloma are also discussed.
Highlights
Multiple myeloma (MM), characterized with malignant clonal expansion of plasma cells in bone marrow with defective production of monoclonal gammopathy, is the second most common hematologic malignancy, which accounts for 13% of all hematologic malignancies and 1% of all cancers in the world [1,2]
It has been noted that the insulin-like growth factor-1 (IGF-1)/IGF-1R signaling pathway is constitutively activated in bortezomib-resistant MM cells lines, and that the serum concentration of IGF-1 is far higher in bortezomib-refractory patients than those who show a response to the drugs
Other myeloid cells involved in myeloma progression, such as megakaryocytes and eosinophils, are involved in the survival of plasma cells by production of IL-6 and A proliferation-inducing ligand (APRIL) that promote the survival of myeloma cells [131]
Summary
Multiple myeloma (MM), characterized with malignant clonal expansion of plasma cells in bone marrow with defective production of monoclonal gammopathy, is the second most common hematologic malignancy, which accounts for 13% of all hematologic malignancies and 1% of all cancers in the world [1,2]. These mechanisms, including chromosome abnormalities, gene mutations, modifications of the bone marrow microenvironment with soluble factors, and/or adhesion of components and cells, all work together to tune the signal pathways that suppress the immune response and promote MM proliferation, survival, and drug resistance Knowing these mechanisms turns on a niche for a novel therapeutic strategy to overcome drug resistance for disease treatment [31,32,33,34]. Knowing the nuclear factor erythroid-derived-2-like 2 (NRF2) is the master regulator of ROS detoxification and associated drug resistance of cancer cells [37], this narrative review will discuss the functional roles of NRF2 in bone marrow microenvironment components. A recent review article described the tumor suppressive and tumor promoting effects of NRF2 in several hallmarks of cancer, underlining the potential of targeting this transcription factor for anticancer therapy [54]
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