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Blood. 2011 Jul 14;118(2):413-5. Epub 2011 May 20.

CirculatingmicroRNAs let-7a and miR-16 predict progression-free survival and overall survival in patients with myelodysplastic syndrome.

Circulating microRNAs let-7a and miR-16 predict progression-free survival and overall survival in patients with myelodysplastic syndrome



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1. Zhuang Zuo1,
2. George A. Calin2,
3. Henrique M. de Paula1,
4. L. Jeffrey Medeiros1,
5. Michael H. Fernandez1,
6. Masayoshi Shimizu2,
7. Guillermo Garcia-Manero3, and
8. Carlos E. Bueso-Ramos1
Author Affiliations
9.  
   1. 
      Departments of ¹Hematopathology, [i]
   2. 
      [i]²Experimental Therapeutics, and [i]
   3. 
      [i]³Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX [i]
   
   
   Abstract
   
   Circulating microRNAs (miRNAs) are potential biomarkers for cancer. We examined plasma levels of 2 miRNAs, let-7a and miR-16, in 50 patients with myelodysplastic syndrome (MDS) and 76 healthy persons using quantitative real-time PCR. Circulating levels of both miRNAs were similar among healthy controls but were significantly lower in MDS patients ([i]P = .001 and P < .001, respectively). The distributions of these 2 miRNA levels were bimodal in MDS patients, and these levels were significantly associated with their progression-free survival and overall survival (both P < .001 for let-7a; P < .001 and P = .001 for miR-16). This association persisted even after patients were stratified according to the International Prognostic Scoring System. Multivariate analysis revealed that let-7a level was a strong independent predictor for overall survival in this patient cohort. These findings suggest that let-7a and miR-16 plasma levels can serve as noninvasive prognostic markers in MDS patients.
   
   Introduction
   
   Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders characterized by abnormalities of bone marrow hematopoietic cells and the microenvironment. MDS patients have a variable risk of transformation to acute myeloid leukemia, and transformation is believed to be a multistep process that requires the accumulation of genetic and epigenetic alterations., Alterations in apoptosis and proliferation have been implicated in the pathogenesis of MDS, but the mechanisms underlying these alterations are incompletely understood. The widely used risk model, the International Prognostic Scoring System (IPSS), integrates cytogenetics, morphology, and clinical features but is limited in its ability to predict MDS patient outcomes.– Molecular markers are needed to improve prediction accuracy.
   
   MicroRNAs (miRNAs) are a recently discovered class of short (19-25 nt), naturally occurring, single-stranded RNA molecules that are components of the epigenetic machinery. MiRNAs regulate the expression of target genes posttranscriptionally, mostly by inhibiting translation or inducing mRNA degradation. MiRNAs also play important roles in the regulation of DNA methylation and histone modification and can function as oncogenes, tumor suppressor genes, or both. MiRNAs have been specifically implicated in the development of solid and hematopoietic malignancies. Recently, miRNAs were identified in several types of body fluid, from both healthy individuals and patients with various types of cancer, and may therefore have potential as noninvasive biomarkers of cancer.– One recent study found that plasma levels of miR-92 may be a biomarker for acute myeloid leukemia.
   
   Two miRNAs, let-7a and miR-16, are known to play important roles in myeloid leukemogenesis by regulating the cell cycle and apoptosis,– both of which are important in MDS pathogenesis. We decided to focus on these 2 miRNAs that are known to be down-regulated in leukemias. The goal of the present study was to analyze the levels of let-7a and miR-16 in plasma samples from MDS patients to assess their potential clinical significance.
   
   Methods
   
   We retrospectively measured circulating levels of miRNAs let-7a and miR-16 in plasma samples from 50 randomly selected MDS patients who were seen at The University of Texas M. D. Anderson Cancer Center between 2004 and 2008 and from 76 healthy control individuals. The MDS patients had a median age of 73 years (range, 38-91 years) and a male-to-female ratio of 2:1. The MDS patient cohort represented the major pathologic groups defined in the 2008 World Health Organization classification of MDS and included the following: 25 patients with refractory cytopenia with multilineage dysplasia, 13 with refractory anemia with excess blasts (RAEB)-1, 9 with refractory anemia with excess blasts (RAEB)-2, 1 with MDS associated with isolated del(5q), 1 with refractory anemia with ring sideroblasts, and 1 with unclassified MDS (). These patients were also stratified according to their IPSS risk scores into 3 groups: low, intermediate-1, and intermediate-2. The 76 healthy control subjects were blood donors at The University of Texas M. D. Anderson Cancer Center. “Healthy” was defined as the absence of any type of infection or known medical condition at the time of study. Written informed consent was obtained from all participants in accordance with the Declaration of Helsinki, and the study was approved by the M. D. Anderson Cancer Center institutional review board.
   
   View this table:
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   Table 1
   
   Clinicopathologic characteristics and survival of MDS patients according to circulating let-7a and miR-16 levels
   
   MiRNA levels were detected by quantitative real-time PCR with TaqMan miRNA assays (Applied Biosystems), with miR-192 as an internal control for plasma RNA normalization, as described previously. The relative expression level of each miRNA was calculated from the equation 2?ΔCt, where ΔCt = mean CtmiRNA?mean Ctinternal control. Differences in miRNA levels were compared with the Student t test. Fisher exact and χ2 tests were applied to categorical variables. The Kaplan-Meier method was used to generate overall survival (OS) and progression-free survival (PFS) curves. PFS was defined as time to progression to acute myeloid leukemia. Survival curves were compared with the log-rank test. To determine whether age, sex, morphology, IPSS score, or miRNA level were independent predictive factors for OS, we performed a multivariate analysis using the Cox proportional hazard model.
   
   Results and discussion
   
   We found that let-7a and miR-16 levels were stable in plasma of healthy control subjects. The relative mean level of let-7a was 23.78 ± 15.43 and that of miR-16 was 1140.01 ± 828.23. Levels of both miRNAs followed a gaussian distribution among the tested group (A-B). Others have reported similar observations. Levels of both miRNAs were significantly lower in MDS patients (5.19 ± 37.51 for let-7a [P = .001] and 83.94 ± 337.77 for miR-16 [P < .001]), with each miRNA showing a bimodal distribution (C-D). We therefore set an arbitrary cutoff value for each miRNA at the lowest frequency point between the 2 distribution peaks and divided the patients into high and low groups. The mean relative levels of let-7a were 28.97 ± 88.50 and 0.01 ± 0.02 in the high and low groups (P = .043), respectively, and those of miR-16 were 348.85 ± 719.81 and 9.24 ± 15.09 (P = .005), respectively. View larger version:
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   Figure 1
   
   Levels of let-7a and miR-16 and survival in patients with MDS and control subjects. Distributions of let-7a and miR-16 plasma levels in 76 healthy control subjects (A-B) and 50 MDS patients (C-D), along with Kaplan-Meier curves showing (E) OS by IPSS risk score (P = .022), (F) PFS by IPSS risk score (P = .063), (G) OS by let-7a level (P < .001), (H) PFS by let-7a level (P < .001), (I) OS by miR-16 level (P = .001), and (J) PFS by miR-16 level (P < .001). INT indicates intermediate.
   
   IPSS score was significantly associated with OS (P = .022) in these MDS patients, but it was not significantly associated with PFS (P = .063; E-F). We further plotted OS and PFS according to miRNA plasma levels. We found that miRNA levels predicted OS and PFS in the MDS patient group (G-J; supplemental Table 1). Moreover, miRNA level could be used to further stratify patients in each IPSS category into different survival groups (supplemental Figure 1A-D). Similar results were obtained with a new risk model proposed by the M. D. Anderson Cancer Center (supplemental Figure 2A-H). On multivariate Cox analysis (supplemental Table 2), we found that an IPSS score of intermediate-2 and a high let-7a level were independent predictive factors for OS (hazard ratio 4.99, 95% confidence interval 1.60-15.59, P = .006, and hazard ratio 5.18, 95% confidence interval 1.62-16.60, P = .006, respectively). The levels of let-7a and miR-16 did not correlate significantly with cytopenia (P = .490 and .176, respectively) or karyotype (P = .425 and .467, respectively) in the present study cohort.
   
   Let-7a is a tumor suppressor gene that regulates oncogenes such as RAS and HMGA2,, and miR-16 targets multiple oncogenes, including BCL2, MCL1, CCND1, and WNT3A. Both of these miRNAs are down-regulated in chronic lymphocytic leukemia, pituitary adenomas, and prostate carcinoma.,, Decreased MiR-16 expression also has been found in blasts isolated from high-risk MDS patients. The exact mechanisms by which circulating miRNAs regulate certain biologic functions are unknown. Previous findings have suggested that miRNAs function as “extracellular communication RNAs” that play an important role in cell proliferation and differentiation., If true, the findings we report suggest that antiproliferative and proapoptotic miRNA activities are down-regulated in the extracellular environment during the phase of MDS when cells in the bone marrow undergo massive apoptosis. These activities, however, are up-regulated when MDS progresses into a proliferative phase.
   
   This is the first report in which plasma miRNA levels in MDS patients have been assessed. We found that miR-16 and let-7a levels were significantly different between healthy control subjects and MDS patients, which makes them possible early, noninvasive biomarkers for diagnosis or prognosis of MDS patients. If confirmed by other studies, assessment of plasma levels of let-7a and miR-16 miRNA may add to the current IPSS risk model for predicting MDS patient survival. Our findings also suggest that extracellular miRNAs play important roles in the development and progression of MDS.
   
   Authorship
   
   Contribution: Z.Z. and G.A.C. performed research, analyzed data, and wrote the manuscript; H.M.d.P. collected clinical data; L.J.M. analyzed data and helped to write the manuscript; M.H.F. and M.S. performed experiments; G.G.-M. evaluated clinical characteristics and provided samples; and C.E.B.-R. designed the research, analyzed the data, and wrote the manuscript.
   
   Conflict-of-interest disclosure: The authors declare no competing financial interests.
   
   H.M.d.P. performed this work as a visiting scientist at M. D. Anderson Cancer Center; his current affiliation is Department of Pathology, University of S?o Paulo School of Medicine, S?o Paulo, Brazil.
   
   Correspondence: Zhuang Zuo, MD, PhD, Department of Hematopathology, Unit 194, The University of Texas M. D. Anderson Cancer Center, 8515 Fannin St, Houston, TX 77054; e-mail: .
   
   Acknowledgments
   
   We thank Lionel Santiba?ez and Walter Pagel for their professional review and editing of the manuscript.
   
   This work was supported in part by The University of Texas M. D. Anderson Cancer Center core grant CA16672 (C.B.R.), and by Leukemia SPORE Developmental Research Award (G.A.C.).
   
   Footnotes
   6.  
      • 
        
        The online version of this article contains a data supplement.
         
      • 
        
        The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
         
      
      
      • Submitted January 14, 2011.
      • Accepted May 6, 2011.
      • &copy; 2011 by The American Society of Hematology
   
   
   References
   7.  
      1. ?
         1. Cazzola M,
         2. Malcovati L
         . Myelodysplastic syndromes: coping with ineffective hematopoiesis. N Engl J Med 2005;352(6):536-538.
         
         3. ?
            1. Malcovati L,
            2. Germing U,
            3. Kuendgen A,
            4. et al
            . Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 2007;25(23):3503-3510.
            
            5. ?
               1. Greenberg P,
               2. Cox C,
               3. LeBeau MM,
               4. et al
               . International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89(6):2079-2088.
               
               5. ?
                  1. Swerdlow SH,
                  2. Campo E,
                  3. Harris NL,
                  4. et al.
                     1. Brunning RD,
                     2. Orazi A,
                     3. Germing U,
                     4. et al
                     . Myelodysplastic syndromes/neoplasms, overview. In: Swerdlow SH, Campo E, Harris NL, et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC; 2008. p. 88-93.
                     
                     5. ?
                        1. Kantarjian H,
                        2. O'Brien S,
                        3. Ravandi F,
                        4. et al
                        . Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System. Cancer 2008;113(6):1351-1361.
                        
                        5. ?
                           1. Pellagatti A,
                           2. Cazzola M,
                           3. Giagounidis A,
                           4. et al
                           . Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells. Leukemia 2010;24(4):756-764.
                           
                           5. ?
                              1. Bartel DP
                              . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004;116(2):281-297.
                              
                              2. ?
                                 1. Croce CM
                                 . Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 2009;10(10):704-714.
                                 
                                 2. ?
                                    1. Kosaka N,
                                    2. Iguchi H,
                                    3. Ochiya T
                                    . Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis. Cancer Sci 2010;101(10):2087-2092.
                                    
                                    4. ?
                                       1. Mitchell PS,
                                       2. Parkin RK,
                                       3. Kroh EM,
                                       4. et al
                                       . Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 2008;105(30):10513-10518.
                                       
                                       5. ?
                                          1. Michael A,
                                          2. Bajracharya SD,
                                          3. Yuen PS,
                                          4. et al
                                          . Exosomes from human saliva as a source of microRNA biomarkers. Oral Dis 2010;16(1):34-38.
                                          
                                          5. ?
                                             1. Park NJ,
                                             2. Zhou H,
                                             3. Elashoff D,
                                             4. et al
                                             . Salivary microRNA: discovery, characterization, and clinical utility for oral cancer detection. Clin Cancer Res 2009;15(17):5473-5477.
                                             
                                             5. ?
                                                1. Kosaka N,
                                                2. Izumi H,
                                                3. Sekine K,
                                                4. Ochiya T
                                                . microRNA as a new immune-regulatory agent in breast milk. Silence 2010;1(1):7.
                                                
                                                5. ?
                                                   1. Tanaka M,
                                                   2. Oikawa K,
                                                   3. Takanashi M,
                                                   4. et al
                                                   . Down-regulation of miR-92 in human plasma is a novel marker for acute leukemia patients. PLoS One 2009;4(5):e5532.
                                                   
                                                   5. ?
                                                      1. Calin GA,
                                                      2. Cimmino A,
                                                      3. Fabbri M,
                                                      4. et al
                                                      . MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci U S A 2008;105(13):5166-5171.
                                                      
                                                      5. ?
                                                         1. Aqeilan RI,
                                                         2. Calin GA,
                                                         3. Croce CM
                                                         . miR-15a and miR-16-1 in cancer: discovery, function and future perspectives. Cell Death Differ 2010;17(2):215-220.
                                                         
                                                         4. ?
                                                            1. Cammarata G,
                                                            2. Augugliaro L,
                                                            3. Salemi D,
                                                            4. et al
                                                            . Differential expression of specific microRNA and their targets in acute myeloid leukemia. Am J Hematol 2010;85(5):331-339.
                                                            
                                                            5. ?
                                                               1. Tsang WP,
                                                               2. Kwok TT
                                                               . Let-7a microRNA suppresses therapeutics-induced cancer cell death by targeting caspase-3. Apoptosis 2008;13(10):1215-1222.
                                                               
                                                               3. ?
                                                                  1. Vasilescu C,
                                                                  2. Rossi S,
                                                                  3. Shimizu M,
                                                                  4. et al
                                                                  . MicroRNA fingerprints identify miR-150 as a plasma prognostic marker in patients with sepsis. PLoS ONE 2009;4(10):e7405.
                                                                  
                                                                  5. ?
                                                                     1. Johnson SM,
                                                                     2. Grosshans H,
                                                                     3. Shingara J,
                                                                     4. et al
                                                                     . RAS is regulated by the let-7 microRNA family. Cell 2005;120(5):635-647.
                                                                     
                                                                     5. ?
                                                                        1. Lee YS,
                                                                        2. Dutta A
                                                                        . The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 2007;21(9):1025-1030.
                                                                        
                                                                        3. ?
                                                                           1. Calin GA,
                                                                           2. Dumitru CD,
                                                                           3. Shimizu M,
                                                                           4. et al
                                                                           . Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 2002;99(24):15524-15529.
                                                                           
                                                                           5. ?
                                                                              1. Pons A,
                                                                              2. Nomdedeu B,
                                                                              3. Navarro A,
                                                                              4. et al
                                                                              . Hematopoiesis-related microRNA expression in myelodysplastic syndromes. Leuk Lymphoma 2009;50(11):1854-1859.
                                                                              
                                                                              5. ?
                                                                                 1. Benner SA
                                                                                 . Extracellular “communicator RNA.”. FEBS Lett 1988;233(2):225-228.
                                                                                 
                                                                                 2. ?
                                                                                    1. Valadi H,
                                                                                    2. Ekstrom K,
                                                                                    3. Bossios A,
                                                                                    4. Sjostrand M,
                                                                                    5. Lee JJ,
                                                                                    6. Lotvall JO
                                                                                    . Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007;9(6):654-659.
                                                                                    

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