Mir-140-3p and Mir-99B-5p Can Improve the Risk Assessment in Patients with MDS and Normal Karyotype Independently of IPSS-R Category
Authors: Andrade-Campos Marcio , Andres-Coduras Marta , Ramos Fernando , Giraldo Pilar 
Published: October 2019

Abstract
Background: The myelodisplastic syndromes (MDS) is a heterogeneous group of hematological neoplasms secondary to a clonal alteration in the hematological stem cell. There is a relationship with the elderly and their major clinical manifestations reflect a status of progressive bone marrow failure with cytopenias and an elevated risk to transformation to acute myeloid leukemia (AML). The WHO 2008 classification for myeloid malignancies and the use of the revised international prognosis-scoring system (IPSS-R) had permitted to improve both therapy and prognosis approaches. The IPSS-R use the new cytogenetic risk scoring system, based in the presence of cytogenetic alterations clinically implicated in patients' outcomes. However more than 50% of patients with MDS are diagnosed without cytogenetic abnormalities (normal karyotype, NK) and they are classified mostly in the good and intermedium risk categories of IPSS-R, different to their counterparts with cytogenetic abnormalities that are more precisely classified. Epigenetic studies and innovative techniques like multiparameter karyotype, molecular biology or wide genetic sequencing can found biomarkers or alterations related with MDS status in these patients. MicroRNAs (miRNAs) are small non-coding regulatory molecules that act on the promoting or silencing different cellular processes. Few years ago, their relationship with hematological malignancies was evidenced. Here there is described an exploratory work of miRNAs implication on MDS patients and their utility on diagnosis and classification of NK-MDS patients.
Aims: To explore the expression of a profile of miRNAs in patients with MDS and NK, assessing the role of them in the risk stratification.
Patients and methods: Based on previous works of our group (Andres-Coduras, et al, ELN 2012; Andres-Codura, et al, SEHH 2013), a miRNAs profile, composed by 14 miRNAs over more than 7,000 miRNAs, was identified, on 40 patients with MDS compared to controls. This profile was analyzed in 243 plasma samples from patients with MDS at diagnosis from the INBIOMED group, previously ethic committee and board approval were required and patients signed an inform consent according the Helsinki declaration revised in 2013. Here, we are presenting a subanalysis including only patients with NK. The miRNA profile included: hsa-miR-26a, hsa-miR-451, hsa-miR-99b, hsa-miR-24, hsa-miR-625, hsa-miR-15b, hsa-miR-19b, hsa-let-7e, hsa-miR-16, hsa-miR-140-3p, hsa-miR361-3p, hsa-miR-378 and hsa-miR-942.
Results: From 154 plasma of NK-MDS patients. All of them classified as very good, good and intermediate risk category by IPSS-R or low and intermedium-1 by IPSS, a total of 143 have associated follow-up information at 2 years of diagnosis. Thirty-seven patients evolved to AML or died in this time. 4 miRNAs differentially expressed (miRNA140-3p, miRNA-15b, miRNA-99b-5p and miRNA-361-3p) showed advantage to identified patients with MDS. Based in IPSS-R, patients were classified as good prognosis group (no candidates to therapy) and high risk group (candidates to therapy). An increase in both the expression of miR-140-3p and miR-99b-5p was able to identified patients with MDS and NK with good prognosis independently of IPSS-R risk category, improving the identification of patients with good outcomes (ROC curve for IPSS-R: 0,669 and for miRNAs model: 0,785), contrary, the underexpression of both miRNAs was a predictor of worse outcomes.
Comments: Here we describe a non-previously described signature of miRNAs that can improve the classification of MDS patients without cytogenetic alterations, especially for patients with good or intermediate risk group. miRNAs could be a good biomarkers during follow-up considering their variations and easy assessment.

Disclosures
Ramos: Amgen: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.