MET dysregulation is a hallmark of aggressive disease in multiple myeloma patients

Abstract

SummaryAbnormal activation of MET/HGF (Hepatocyte Growth Factor) pathway has been described in several tumours and increased HGF plasmatic levels have been detected in patients with aggressive multiple myeloma (MM). MET and HGF mRNA expression was investigated in 105 samples of purified plasma cells derived from newly diagnosed MM patients treated with bortezomib-based induction therapy. Gene expression was compared with response to therapy and clinical outcome. MET gene copy number was also evaluated. MET mRNA expression was higher in CD138 + than in CD138 À cells (median 76Á90 vs. 11Á24; P = 0Á0009). Low MET mRNA expression characterized patients with better response (complete response or very good partial response) compared to other patients (median 56Á10 vs. 134Á83; P = 0Á0006). After a median follow-up of 50 months, patients with high MET mRNA expression displayed a worse progression-free survival (PFS; P = 0Á0029) and overall survival (OS; P = 0Á0023) compared to those with low MET mRNA levels. Patients with both high MET mRNA expression and high b2-microglobulin level (>5Á5 mg/l) had further worse median PFS (P < 0Á0001) and OS (P < 0Á0001). Patients carrying 4 MET gene copies (8 out of 82, 9Á8%) also had a short PFS. High MET mRNA expression identifies patients with dismal PFS and OS and the combination with high b2-microglobulin further characterizes patients with worse outcome.

A HGF/cMET Autocrine Loop Is Operative in Multiple Myeloma Bone Marrow Endothelial Cells and May Represent a Novel Therapeutic Target

“…Rocci and colleagues (39) reported that the overexpression of the cMET oncogene in PCs indicates poor prognosis. Overall, an altered HGF/cMET pathway activation in multiple myeloma PCs implies a less responsive disease.…”

MET/HGF pathway in multiple myeloma: from diagnosis to targeted therapy?

“…[55] These results have been confirmed in vivo by our study, showing that low MET mRNA expression in PCs identified patients with a better response to bortezomib-based treatment. [46] A consistent increase in MET expression has been observed in patients achieving a CR compared with those exhibiting stable disease. Median MET mRNA expression was 56.10 in patients achieving at least a VGPR but was 134.83 in those achieving only a PR or a SD.…”

“…Similarly, the overexpression of MET mRNA in PCs of MM patients was also associated with low response to therapy and poor clinical outcome. [46] We investigated MET mRNA expression in 105 newly diagnosed MM patients treated with bortezomib-based therapy. The crude analysis of clinical outcome in the group of patients with high vs low MET mRNA expression (median value was used as a cutoff) showed a better prognosis in patients with low MET expression.…”

“…Like western blotting, this method is used to evaluate the expression mostly in MM cell lines since often the amounts of primary cells are limited. [39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] Moreover, the use of flow cytometry is already part of diagnostic procedure in some institutions and only minimal arrangements are required to include this analysis into the existing workflow.…”

“…[58][59] We performed a specific investigation of MET gene copy number in 82 MM patients and the ratio between MET gene and control gene was used to define MET status. [46] This was the first paper investigating the presence of MET amplification in MM, although a higher number of patients are required in order to set the specific cut-off in this particular disease.…”