MicroRNA Expression-Based Model Indicates Event-Free Survival in Pediatric Acute Myeloid Leukemia

Abstract

PurposeChildren with acute myeloid leukemia (AML) whose disease is refractory to standard induction chemotherapy therapy or who experience relapse after initial response have dismal outcomes. We sought to comprehensively profile pediatric AML microRNA (miRNA) samples to identify dysregulated genes and assess the utility of miRNAs for improved outcome prediction.Patients and MethodsTo identify miRNA biomarkers that are associated with treatment failure, we performed a comprehensive sequence-based characterization of the pediatric AML miRNA landscape. miRNA sequencing was performed on 1,362 samples—1,303 primary, 22 refractory, and 37 relapse samples. One hundred sixty-four matched samples—127 primary and 37 relapse samples—were analyzed by using RNA sequencing.ResultsBy using penalized lasso Cox proportional hazards regression, we identified 36 miRNAs the expression levels at diagnosis of which were highly associated with event-free survival. Combined expression of the 36 miRNAs was used to create a novel miRNA-based risk classification scheme (AMLmiR36). This new miRNA-based risk classifier identifies those patients who are at high risk (hazard ratio, 2.830; P ≤ .001) or low risk (hazard ratio, 0.323; P ≤ .001) of experiencing treatment failure, independent of conventional karyotype or mutation status. The performance of AMLmiR36 was independently assessed by using 878 patients from two different clinical trials (AAML0531 and AAML1031). Our analysis also revealed that miR-106a-363 was abundantly expressed in relapse and refractory samples, and several candidate targets of miR-106a-5p were involved in oxidative phosphorylation, a process that is suppressed in treatment-resistant leukemic cells.ConclusionTo assess the utility of miRNAs for outcome prediction in patients with pediatric AML, we designed and validated a miRNA-based risk classification scheme. We also hypothesized that the abundant expression of miR-106a could increase treatment resistance via modulation of genes that are involved in oxidative phosphorylation.

Genomic testing in myeloid malignancy

“…Newer RNA‐seq protocols will be able to provide useful information on lncRNAs and other RNA species. MicroRNAs have many demonstrated roles in AML pathogenesis, and miRNA expression signatures have also been used to predict event‐free survival in pediatric AMLs . Recent work has identified the recurrence of common splicing mutations in myeloid malignancies.…”

“…MicroRNAs have many demonstrated roles in AML pathogenesis, 54 and miRNA expression signatures have also been used to predict event-free survival in pediatric AMLs. 55 Recent work has identified the recurrence of common splicing mutations in myeloid malignancies. Inference of the particular downstream splicing changes induced by these alterations is likely to be important for identifying precision therapies.…”

Identification of Acute Myeloid Leukemia Bone Marrow Circulating MicroRNAs

“…In a previous study, we demonstrated that this miRNA negatively regulates IFN-γ expression in T lymphocytes [ 83 ], and recently, we showed its direct impact on AML T lymphocyte fragility and dysfunction (in preparation). Furthermore, other downregulated miRNAs in CR1, such as miR-15b [ 84 ], miR-27a [ 85 ], miR-29c [ 86 ], miR-106a [ 87 ] and miR-181a [ 88 ], have been described as being implicated in AML pathogenesis or drug resistance.…”

Essential gene networks in acute myeloid leukemia identified using a microRNA-knockout CRISPR library screen

“…It is possible that these genes may not be highly expressed or to have discreet effects at low expression status. Given the likelihood of interaction of each miRNA with several downstream gene targets, it is possible that signatures involving several miRNA may prove better predictors than any single miRNA alone [62].…”