Abstract B34: Increased risk of relapse in non-high-risk children with pediatric B-lineage acute lymphoblastic leukemia can be predicted at diagnosis by microRNA expression
Authors: Avigad Smadar , Verly Iedan RN , Kaspers Gertjan JL , Cloos Jacqueline , Ohali Anat , Hameiri-Grossman Michal , Shichrur Keren , Fronkova Eva , Trka Jan , Luria Drorit , Kodman Yona , Mirsky Hadar , Gaash Dafna , Jeison Marta , Avrahami Galia , Elitzur Sarah , Gilad Gil , Stark Batia , Yaniv Isaac 
Published: May 2015

Abstract
Aim: microRNAs (miRNAs) have been implicated in many malignancies. Our aim was to identify specific miRNAs that can predict risk of relapse in pediatric acute lymphoblastic leukemia (ALL) patients treated on BFM protocols, better than the current risk group stratification. Currently, the main method for risk group stratification is based on the amount of minimal residual disease (MRD) assessed at specific time points by real time quantitative PCR (RQ-PCR).
Material and methods: Following microRNA expression analysis, we decided to focus on miR-151-5p and miR-451 that significantly correlated with known prognostic factors in ALL. Validation was performed by measuring the expression levels of miR-151-5p and miR-451 by RQ- PCR on a cohort of B-lineage ALL patients treated by a Berlin-Frankfurt-Munster (BFM) protocol following exclusion of Philadelphia positive patients (n=123).
Results: Low expression of miR-151-5p, miR-451 or of both together resulted in significantly worse relapse free survival (RFS) (61%, 64% and 43%, respectively) compared to RFS rates when either or both miRNAs were highly expressed (83%, 82% and 82%, respectively) (p=0.023, 0.03 and 0.0001, respectively). Multivariate Cox regression analysis identified low expression of both miRNAs as an independent prognostic marker. Patients expressing low expression levels of both miRs had a 8.8-fold increased risk for relapse (p=0.003). Deletion of IKZF1 gene is a known adverse prognostic marker in B-lineage ALL. In 88 patients, IKZF1 status was analyzed and 9 patients were found to harbor the deletion. The expression of both miRs could still identify an adverse group of patients with only 50% RFS within the group with no deletion (p&lt;0.0003).
Even in a non-BFM treated B-lineage ALL cohort from The Netherlands, the expression levels of both miRs significantly correlated with outcome (p=0.003).
Conclusion: Our results identify miR-151-5p and miR-451 as novel biomarkers for outcome in pediatric B-lineage ALL patients, regardless of treatment protocol. This may lead to improved risk group stratification and better RFS.
Citation Format: Smadar Avigad, Iedan RN Verly, Gertjan JL Kaspers, Jacqueline Cloos, Anat Ohali, Michal Hameiri-Grossman, Keren Shichrur, Eva Fronkova, Jan Trka, Drorit Luria, Yona Kodman, Hadar Mirsky, Dafna Gaash, Marta Jeison, Galia Avrahami, Sarah Elitzur, Gil Gilad, Batia Stark, Isaac Yaniv. Increased risk of relapse in non-high-risk children with pediatric B-lineage acute lymphoblastic leukemia can be predicted at diagnosis by microRNA expression. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B34.