miRNA Repression May Drive Aberrant Signaling in MM

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Repression of the microRNA miR-375 may be the primary mechanism underlying the constitutive activation of PDPK1/RPS6KA3 signaling in multiple myeloma.
Repression of the microRNA miR-375 may be the primary mechanism underlying the constitutive activation of PDPK1/RPS6KA3 signaling in multiple myeloma.

Repression of the microRNA miR-375 may be the primary mechanism underlying the constitutive activation of PDPK1/RPS6KA3 signaling in multiple myeloma (MM), according to an in vitro study published in the British Journal of Haematology.1

Previous studies showed that PDPK1/RPS6A3 signaling is constitutively active in MM and is critical for its pathophysiology. This study investigated the role of aberrant miR-375 repression in PDPK1 overexpression.

The in vitro study evaluated plasma cells from 30 patients with monoclonal gammopathies of undetermined significance (MGUS), 34 with newly diagnosed MM, 39 with relapsed/refractory MM, and 10 healthy donors. The diagnosis of MGUS vs MM was made according to the 2014 International Myeloma Working Group criteria. The study also used 11 human myeloma cell lines (HMCLs).

miR-375 expression was significantly lower in MGUS and MM plasma cells compared with normal plasma cells (P < .05 and < .01, respectively). There was no difference in expression levels between plasma cells of patients with MGUS, newly diagnosed MM, relapsed/refractory MM, or the HMCLs.

Expression of miR-375 was not associated with the type of chromosomal abnormality observed among the patients with MM.

HMCLs treated with miR-375 demonstrated decreased PDPK1 expression, suggesting that miR-375 could regulate PDPK1 expression. miR-375 also decreased the expression of IGF1R and JAK2.

Two CPG islands — CGI-1 and CGI-2 — were highly methylated in MGUS, MM plasma cells, and HMCLs, suggesting epigenetic modulation. Hypermethylation was present in 72% of MGUS and MM samples for CGI-1 and 57% for CGI-2.

Treatment of HMCLs with a hypomethylating agent or a histone deacetylase inhibitor increased miR-375 expression and decreased the expression of PDPK1, IGF1R, and JAK2.

Serum levels of miR-375 were, however, similar between healthy donors and patients with MM. According to the authors, this indicates that “abnormal repression of miR-375 is an event specific to myeloma cells, and not a systemic event in normal tissues in MM patients.”

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“This study revealed that expression of miR-375 is pathologically and universally decreased in clonal plasma cells from MGUS to relapsed/refractory MM patients,” wrote the authors. They suggested that these findings may be useful for developing novel therapies targeting miR-375.

Reference

  1. Tatekawa S, Chinen Y, Ri M, et al. Epigenetic repression of miR-375 is the dominant mechanism for constitutive activation of the PDPK1/RPS6KA3 signalling axis in multiple myeloma. Br J Haematol. 2017 Apr 25. doi: 10.1111/bjh.14707 [Epub ahead of print]

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