HIGH LEVELS OF NEURAL STEM CELL MARKER NESTIN ARE ASSOCIATED WITH 1Q21 GAIN AND PREDICT WORSE RESPONSE TO CONVENTIONAL AND NOVEL THERAPY IN MULTIPLE MYELOMA

Sborník

Backround. Nestin, an intermediate filament protein, is detected in undifferentiated multipotent cells of some embryonic and fetal tissues. During terminal differentiation, nestin expression is diminished but may be reexpressed under certain pathological conditions, such as injury or cancer. Nestin is a suitable diagnostic and prognostic indicator of malignancy and potential cancer stem cells marker in solid tumors. Our recent work confirmed nestin protein as a tumorspecific marker for CD138+38+ plasma cells (PC) and proved significant higher nestin levels in multiple myeloma (MM) compared with controls without any hematological malignancy. Aims. The aim of this study was i) to analyze relationship between nestin expression and cytogenetic aberrations in CD138+PC, ii) to analyze relationship between nestin and standard prognostic parameters and iii) evaluate whether pretreatment levels of nestin predict response to therapy. Methods. A total number of 93 newly diagnosed MM patients (36M/47F; median age 70 years) were enrolled in this study. Gene expression of nestin was analyzed by quantitative real-time PCR in 70.9% (66/93) of MM patients and quantified by the comparative ddCt method. Nestin was detected in CD138+38+PC of 50.5% (47/93) of MM patients and 10 individuals without hematological malignancy by flow cytometry. Nestin levels were assessed as the percentage of nestin-positive PC (%Nes+PC) and ratio of median fluorescence intensity of nestin (MFI) and isotypic control. CD138+PC of MM patients were analyzed for del(13q14), del(17p53), IgH rearrangement, 1q21 gain and hyperdiploidy by FISH. Pretreatment levels of nestin mRNA and protein were evaluated in MM patients treated with conventional therapy or novel agents without autologous stem cell transplantation. Differences among groups were analyzed by non-parametric Mann-Whitney U test or Kruskall Wallis H test. Correlation was analyzed by Spearman correlation coefficient. Results. Significant differences between MM patients and the control group were demonstrated based on %Nes+PC (98.5 vs. 0.1; p<0.00001) and MFI ratio (3.5 vs. 2.0; p<0.0001). High %Nes+PC (p=0.007) and MFI ratio (p=0.012) were significantly associated with 1q21 gain-positive patients. No correlation between gene or protein expression of nestin and standard prognostic parametres was confirmed. Differences of MFI ratio between patients who achieved at least VGPR and patients with worse response reached only borderline significance (p=0.053). Patients who achieved ≥VGPR had lower nestin expression compared with patients who achieved ≤PR [median RQ 1.3(0.6-3.9) vs median RQ 4.6(1.7-152.0); p=0.001]. Conclusions. MM patients have significantly higher levels of nestin protein and percentage of Nes+PC compared with the control group. The association with 1q21 gain may be explained by the fact that nestin gene is located at 1q23.1 and gain of whole q-arm of chromosome 1 is found in most MM patients. Relationship between nestin and other prognostic parameters was not proved. High levels of nestin mRNA appear to be a potential predictor of worse response in patients treated with conventional therapy or novel agents. This pilot study needs to be further validated on a larger cohort of patients.

Funded by MSM P304/10/1395 and MSM 0021622434

Haematologica, 2012; 97(s1):  16