Page 72 - Haematologica July

Haematologica 2018 Volume 103(7):1150-1159
Ferrata Storti Foundation
Bone Marrow Failure
Circulating exosomal microRNAs in acquired aplastic anemia and myelodysplastic syndromes
Valentina Giudice,1 Lauren G. Banaszak,1 Fernanda Gutierrez-Rodrigues,1 Sachiko Kajigaya,1 Reema Panjwani,1 Maria del Pilar Fernandez Ibanez,1
Olga Rios,1 Christopher K. Bleck,2 Erin S. Stempinski,2 Diego Quinones Raffo,1 Danielle M. Townsley1 and Neal S. Young1
1Hematology Branch and 2Electron Microscopy Core Facility, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA
ABSTRACT
Exosomal microRNAs modulate cancer cell metabolism and the immune response. Specific exosomal microRNAs have been report- ed to be reliable biomarkers of several solid and hematologic malig- nancies. We examined the possible diagnostic and prognostic values of exosomal microRNAs in two human bone marrow failure diseases: aplastic anemia and myelodysplastic syndromes. After screening 372 microRNAs in a discovery set (n=42) of plasma exosome samples, we constructed a customized PCR plate, including 42 microRNAs, for vali- dation in a larger cohort (n=99). We identified 25 differentially expressed exosomal microRNAs uniquely or frequently present in aplastic anemia and/or myelodysplastic syndromes. These microRNAs could be related to intracellular functions, such as metabolism, cell survival, and prolifer- ation. Clinical parameters and progression-free survival were correlated to microRNA expression levels in aplastic anemia and myelodysplastic syndrome patients before and after six months of immunosuppressive therapy. One microRNA, mir-126-5p, was negatively correlated with a response to therapy in aplastic anemia: patients with higher relative expression of miR-126-5p at diagnosis had the shortest progression-free survival compared to those with lower or normal levels. Our findings suggest utility of exosomal microRNAs in the differential diagnosis of bone marrow failure syndromes. (Registered at clinicaltrials.gov identifiers: 00260689, 00604201, 00378534, 01623167, 00001620, 00001397, 00217594).
Introduction
The bone marrow (BM) failure syndromes are a heterogeneous group of hema- tologic diseases characterized by peripheral blood (PB) cytopenia due to hematopoietic stem and progenitor cell (HSPC) destruction and dysfunction, and/or constitutional syndromes due to genetic lesions.1-3 Blood count improve- ment after immunosuppressive therapies (IST) implicates autologous immune- mediated HSPC destruction in aplastic anemia (AA).4 Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal pre-malignant diseases characterized by ineffective hematopoiesis, progressive cytopenias, increased risk of developing acute myeloid leukemia (AML), and poor overall survival.2,5 However, approximate- ly 10-15% of MDS cases share clinical and pathological features with AA, in a sub- type known as hypocellular MDS; conversely, 10-15% of patients with BM failure ultimately develop secondary MDS after IST, suggesting that AA and MDS have common mechanisms in pathophysiology and disease progression.6,7 Despite the discovery of new molecular biomarkers, the differential diagnosis between BM failure syndromes and their prognosis is still challenging.8
In an effort to improve the definition of these hematologic disorders, circulating microRNAs (miRNAs, small non-coding RNA molecules of about 22 nucleotides),
Correspondence:
valentina.giudice@nih.gov
Received: October 20, 2017. Accepted: April 18, 2018. Pre-published: April 19, 2018.
doi:10.3324/haematol.2017.182824
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/7/1150
©2018 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
1150
haematologica | 2018; 103(7)
ARTICLE