New insights into hypoxia-driven metabolic, anti-apoptotic and immune evasion strategies of primary human myeloma cells

ABSTRACT: Multiple Myeloma (MM) is an incurable plasma cell malignancy primarily localized within the bone marrow (BM). It develops from a premalignant stage, monoclonal gammopathy of undetermined significance (MGUS), often via an intermediate stage, smoldering MM (SMM). The mechanisms of MM progression have not yet been fully understood, all the more because patients with MGUS and SMM already carry the same initial mutations found in MM cells. Over the last years, more and more importance has been attributed to the tumor microenvironment and its role in the pathophysiology of the disease. Adaptations of MM cells to the hypoxic conditions in the BM have been shown to contribute to a significant extent to MM progression, independently from the genetic predispositions of the tumor cells. To get deeper insights into such hypoxia-induced adaptations, we decided to investigate primary human MM cells. CD138-positive plasma cells freshly isolated from the BM of patients with different disease stages, comprising MGUS, SMM, and MM, were analyzed by proteome profiling using a Q Exactive orbitrap. Data previously obtained from peripheral B cells were included for comparative purposes. As a first, rather unexpected result, we were able to identify three clusters differentiating B cells as well as MM cells corresponding to less and more advanced disease stages. Comparing on the one hand B cells to MM cells, and on the other hand the two clusters of MM cells allowed us to determine transcription factors apparently involved in MM development and progression, as well as protein regulatory networks obviously related to metabolic adaptations and immune evasion strategies used by MM cells to overcome limitations imposed by hypoxia. Based on these results, new opportunities may arise for developing therapeutic strategies targeting the progression from less to more advanced stages of MM.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Plasma Cell, Bone Marrow

DISEASE(S): Multiple Myeloma

SUBMITTER: Astrid Slany  

LAB HEAD: Christopher Gerner

PROVIDER: PXD010600 | Pride | 2019-02-27

REPOSITORIES: Pride