Role Of miRNA Expression As Novel Biomarker Of GvHD After Allogeneic Stem Cell Transplantation

MicroRNAs (miRNAs) are a family of 19-24 nucleotide noncoding RNAs, which affect the regulation of gene expression in eukaryotic cells by binding to a 3´-untranslated region which target messenger RNAs. MiRNAs plays important roles in many cellular processes such as development, stem cell division, apoptosis and cancer. We profiled miRNAs expressed on patients (pts) who underwent allogeneic hematopoietic stem cell transplantation (HSCT).

Here we analyzed in a retrospective study 258 pts (male 124 pts, female 134 pts) for miRNAs expression (miRNA-21; -128; -146; -155; -181; and –let7) in whole blood at different time-points that underwent allogeneic HSCT and analyzed their outcome. MiRNA expressions were performed by miRNA-specific real time RT-PCR.

In this cohort 84 pts received grafts from HLA-identical siblings (32%), 126 pts from matched (49%) and 48 pts from mismatched (19%) unrelated donors. Transplant consisted of unmanipulated peripheral blood stem cells (n=225, 87%) or bone marrow (n=33, 13%). Of all pts, 64 (25%) had relapsed and 41 (16%) died of June 2013. There was no significant correlation between miRNA expressions from siblings and unrelated donors. For miRNA-181, we found a significant up-regulation in mismatched unrelated donors versus matched donors (489 vs. 330%, p<0.005). Analysis of each miRNAs for relapse showed no statistically differences. Among all pts, 210 (81%) developed acute GVHD (93 pts had an aGvHD of grade ≥2). There was a significant differences between low level of miRNA-146 (529 ± 516% vs. 804 ± 1335%; p<0.04), and high level of miRNA-let7 (642 ± 419% vs. 546 ± 335%, p<0.05) of pts with aGvHD ≥ 2. In pts with severe aGVHD (grade >3) comparing all other aGvHD pts., we found a high significant reductions of miRNA-146 (333% vs. 720%, p<0.001), and miRNA-21 (528% vs. 2356%, p<0.02). In regard to chronic GvHD, we found a down-regulation of miRNA-let7 expressions in pts with severe cGVHD (384% vs. 922%, p<0.002) comparing other cGVHD in the first year. The probability of severe aGvHD with low level of miRNA-146 (< 215%, p<0.001) is 20 ± 7% versus 4 ± 2% with higher levels of miRNA-146 levels. However, an estimate for death in remission or overall survival was not significantly associated with miRNAs.

These results suggest that pts with different expression of miRNA-146, miRNA-21 and miRNA-let7 confirms a relevant association of the development of aGVHD and miRNA profiling could be an early indicator of severe aGvHD.

Off Label Use: HCG will be discussed as new therapy for chronic GVHD.