Abstract
In the era of new and mostly effective therapeutic protocols, multiple myeloma still tends to be a hard-to-treat hematologic cancer. This hallmark of the disease is in fact a sequel to drug resistant phenotypes persisting initially or emerging in the course of treatment. Furthermore, the heterogeneous nature of multiple myeloma makes treating patients with the same drug challenging because finding a drugable oncogenic process common to all patients is not yet feasible, while our current knowledge of genetic/epigenetic basis of multiple myeloma pathogenesis is outstanding. Nonetheless, bone marrow microenvironment components are well known as playing critical roles in myeloma tumor cell survival and environment-mediated drug resistance happening most possibly in all myeloma patients. Generally speaking, however; real mechanisms underlying drug resistance in multiple myeloma are not completely understood. The present review will discuss the latest findings and concepts in this regard. It reviews the association of important chromosomal translocations, oncogenes (e.g. TP53) mutations and deranged signaling pathways (e.g. NFκB) with drug response in clinical and experimental investigations. It will also highlight how bone marrow microenvironment signals (Wnt, Notch) and myeloma cancer stem cells could contribute to drug resistance in multiple myeloma.
Highlights
Multiple myeloma (MM) is the second most common but as yet incurable hematologic malignancy characterized by infiltration in the bone marrow of malignant plasma cells
MM pathogenesis can be largely explained on the basis of interaction of MM cells with bone marrow microenvironment (BMME) components and signaling pathways thereof leading to MM cells growth and survival, angiogenesis, osteolytic lesions and drug resistance (DR)
IL-6 is certainly the best studied cytokine critical to MM cells, which has been implicated in MM cells resistance to various apoptotic signals including Fas/Apo-1 and chemotherapeutic drugs [200,201,202], with these responses being possibly controlled through Jak/STAT signaling pathway as was shown in U266 cell line [203]
Summary
Multiple myeloma (MM) is the second most common but as yet incurable hematologic malignancy characterized by infiltration in the bone marrow of malignant plasma cells. Signals will impinge on mutated oncogenes in latter pathways leading to upregulation of survival and drug resistance or downregulation of cell death responses.
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