Analysis Of Micro-RNA-142 Mutations In a Cohort Of 944 Patients With MDS and AML
Authors: Thol Felicitas , Kirchner Aylin , Shahswar Rabia , Kade Sofia , Koenecke Christian , Stadler Michael , Platzbecker Uwe , Thiede Christian , Schroeder Thomas , Kobbe Guido , Bug Gesine , Ottmann Oliver G. , Hofmann Wolf-Karsten , Kröger Nicolaus , Krauter Juergen , Ganser Arnold , Heuser Michael 
Published: October 2019

Background

MicroRNAs are short (20-40 nucleotides) non-coding RNA molecules that are responsible for the post-transcriptional regulation of gene expression. Aberrant expression of MicroRNAs has been associated with various malignancies. Specifically, downregulation of MicroRNA-142 (miR-142) has been shown to occur in acute myeloid leukemia (AML). Interestingly, also gene mutations in miR-142 have been recently described in de novo AML. So far, little is known about mutations in miR-142 in myeloid malignancies. The aim of this study was to analyze mutations in the miR-142 in a large cohort of 944 patients with AML and myelodysplastic syndrome (MDS).

Patients and Methods

The patient group consisted of 425 de novo AML patients (excluding AML M3) who entered the multicenter treatment trials AML SHG 0199 or AML SHG 0295, 326 patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for secondary acute myeloid leukemia after a prior diagnosis of MDS (sAML) (n=170) or primary MDS (n=156), and 193 primary MDS patients not undergoing intensive therapy or allogeneic HSCT. The genomic region of the miR-142 gene, containing miR-142-5p and miR-142-3p, was sequenced by Sanger sequencing. Patient samples were also assessed for other frequently mutated genes in AML and MDS.

Results and Discussion

We identified five patients with mutations in miR-142. All mutations were heterozygous point mutations affecting the seed region of miR-142-3p, thereby potentially changing the target specificity of miR-142. Mutations in miR-142 occurred in male and female patients. Of the five patients with mutations in miR-142, only one patient carried the diagnosis of de novo AML (0.2% in de novo AML), while two patients were diagnosed with sAML (1.2% in sAML) and two patients had MDS (0.56% in MDS, corresponding to 0.77% in MDS/AML from MDS). Apart from one patient who underwent allogeneic transplantation for sAML, all other patients with follow-up died of the disease in less than a year. 3 patients had normal cytogenetics, while one patient had a complex karyotype and one patient had a trisomy 8 with translocation t(1;4). No mutated patient showed aberrations typically associated with de novo AML (RUNX1/RUNX1T1, CBFB/MYH11, FLT3-ITD, NPM1 mutations or CEBPA mutations). However, myelodysplasia-related gene mutations such as mutations in the splicing genes or chromatin remodelling genes were found in two patients (one patient with mutated ASXL1 and SRSF2, one patient with mutated U2AF1). Furthermore, one patient had a concomitant mutation in NRAS and IDH1. Thus, the associated mutational profile suggests that miR-142 mutations play a role in the pathogenesis of MDS rather than de novo AML.

Conclusion

MicroRNA-142 is recurrently but infrequently mutated in MDS and secondary AML evolving from MDS, and some mutations co-occur with MDS-related gene aberrations. As miR-142 mutations affect the seed region of the miRNA the target specificity is likely changed, and the miRNA may lose its tumor suppressor function, which has been implicated from functional studies.

Disclosures:

Platzbecker: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.