Identification of High Risk Group for Leukemic Transformation in Higher Risk MDS Patients Using Targeted RNA-Sequencing: Hematopoietic Stem Cell Signature As a High Risk Profile for Leukemic Transformation

• Published in: Blood 2018-11, Vol.132 (Supplement 1), p.4361-4361
• Main Authors: Moon, Joon Ho, Kim, Taehyung, Ahn, Jae-Sook, Ahn, Seo-Yeon, Jung, Sung-Hoon, Yang, Deok-Hwan, Lee, Je-Jung, Choi, Seunghyun, Lee, Yoojin, Sohn, Sang Kyun, Kim, Hyeoung-Joon, Zhang, Zhaolei, Kim, Dennis Dong Hwan
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-99-116241

Introduction Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid disorder characterized by defective bone marrow (BM) hematopoiesis with peripheral blood cytopenias and risk for progression to acute myeloid leukemia. Accurate determination of prognosis is critical to select an appropriate therapy and to detect any case progressing to leukemic transformation which brings ominous prognosis in patients with MDS. Despite clinical risk models, additional molecular data are needed to enhance the prediction of patients' clinical courses and to aid disease management. Therefore, the present study attempted to classify the higher risk MDS (HR-MDS) patients according to their molecular risk through targeted RNA-sequencing, to correlate it with clinical risk models, and analyzed molecular risk grouping for prognostic stratification power, especially for leukemic transformation in higher-risk patients with MDS treated with hypomethylating agents (HMA) including azacitidine or decitabine. Patients and Methods A total of 30 patients were included with HR-MDS by International Prognostic Scoring System (IPSS). Overall, 60 bone marrow samples (30 diagnosis and follow-up pairs) were subject for targeted RNA-seq using Illumina TruSight Pan-Cancer panel. After read mapping by Tophat2, gene count was measured using HTSeq followed by DEseq2 for differential gene expression quantification. All 60 samples as well as 30 samples from T-cell fraction (CD3+, as a control) were also subjected for DNA-seq targeting a panel of 84 commonly mutated genes in myeloid malignancies (Agilent SureSelect). All downstream computational and statistical analyses were performed using R and Python. Results The median age was 65 years (range 40-84 years) with 16 male patients (53%). Twenty-seven (90%) and 3 (10%) patients were intermediate-2 and high risk by IPSS, respectively. According to revised IPSS (IPSS-R), the distribution of risk groups was as follows: low (n=5, 17%), intermediate (n=8, 27%), high (n=11, 37%), and very high (n=6, 20%). A total of 56 mutations were detected in the diagnostic samples from 30 patients. Frequently mutated genes were DDX41 (n=5) and TP53 (n=4). Best response to HMA (16 azacitidine and 14 decitabine) was achieved in median 4 cycles (range 3-8). Complete response (CR) including marrow CR was achieved in 18 patients (60%), and 10 patients (33%) received allogeneic hematopoietic cell transplantation. Overall survival (OS) rate was not well correlated wit