MicroRNA characterize genetic diversity and drug resistance in pediatric acute lymphoblastic leukemia

Abstract

The online version of this article has a Supplementary Appendix. BackgroundMicroRNA regulate the activity of protein-coding genes including those involved in hematopoietic cancers. The aim of the current study was to explore which microRNA are unique for seven different subtypes of pediatric acute lymphoblastic leukemia. Design and MethodsExpression levels of 397 microRNA (including novel microRNA) were measured by quantitative real-time polymerase chain reaction in 81 cases of pediatric leukemia and 17 normal hematopoietic control cases. ResultsAll major subtypes of acute lymphoblastic leukemia, i.e. T-cell, MLL-rearranged, TEL-AML1-positive, E2A-PBX1-positive and hyperdiploid acute lymphoblastic leukemia, with the exception of BCR-ABL-positive and 'B-other' acute lymphoblastic leukemias (defined as precursor Bcell acute lymphoblastic leukemia not carrying the foregoing cytogenetic aberrations), were found to have unique microRNA-signatures that differed from each other and from those of healthy hematopoietic cells. Strikingly, the microRNA signature of TEL-AML1-positive and hyperdiploid cases partly overlapped, which may suggest a common underlying biology. Moreover, aberrant down-regulation of let-7b (~70-fold) in MLL-rearranged acute lymphoblastic leukemia was linked to up-regulation of oncoprotein c-Myc (PFDR<0.0001). Resistance to vincristine and daunorubicin was characterized by an approximately 20-fold up-regulation of miR125b, miR-99a and miR-100 (PFDR≤0.002). No discriminative microRNA were found for prednisolone response and only one microRNA was linked to resistance to L-asparaginase. A combined expression profile based on 14 microRNA that were individually associated with prognosis, was highly predictive of clinical outcome in pediatric acute lymphoblastic leukemia (5-year disease-free survival of 89.4%±7% versus 60.8±12%, P=0.001). ConclusionsGenetic subtypes and drug-resistant leukemic cells display characteristic microRNA signatures in pediatric acute lymphoblastic leukemia. Functional studies of discriminative and prognostically important microRNA may provide new insights into the biology of pediatric acute lymphoblastic leukemia.

MicroRNAs in acute leukemia: from biological players to clinical contributors

“…Most striking differences were found for 11q23/ MLL-rearranged precursor B-ALL cases, which displayed downregulation of miR-708 and upregulation of miR-196b and t(12;21)/TEL-AML1-positive precursor B-ALL cases, which distinguished by upregulation of miR-383, miR-125b, miR-99a and miR-100 (Table 1). 22 Remarkably, the miRNA signature of TEL-AML1-positive and hyperdiploid (450 chromosomes) ALL cases partly overlapped similar to what has been observed for mRNA expression profiles, 22,29 which may suggest a common underlying biology. High expression of miR-33, miR-215, miR-369-5p, miR-496, miR-518d and miR-599 was associated with an unfavorable prognosis whereas high expression of other miR-genes (that is, miR-10a, miR-134, miR-214, miR-484, miR-572, miR-580, miR-624 and miR-627) was linked to a favorable prognosis in pediatric ALL.…”

“…[18][19][20][21] Quantitative analysis of 397 miRNAs revealed that leukemic cells of pediatric precursor B-ALL patients have different miRNA expression profiles than samples of normal bone marrow and CD34 þ sorted cells. 22 Moreover, miRNAs were significantly differentially expressed between T-ALL cases and normal thymocytes. 22 Cytogenetically relevant types of ALL in children display characteristic miRNA expression signatures as visualized in Figure 2 (adapted from Schotte et al 22 ).…”

“…22 Moreover, miRNAs were significantly differentially expressed between T-ALL cases and normal thymocytes. 22 Cytogenetically relevant types of ALL in children display characteristic miRNA expression signatures as visualized in Figure 2 (adapted from Schotte et al 22 ). Most striking differences were found for 11q23/ MLL-rearranged precursor B-ALL cases, which displayed downregulation of miR-708 and upregulation of miR-196b and t(12;21)/TEL-AML1-positive precursor B-ALL cases, which distinguished by upregulation of miR-383, miR-125b, miR-99a and miR-100 (Table 1).…”

“…A combined profile of these 14 miR genes further improved the predictive value for long-term clinical outcome in children with ALL. 22 Adult acute myeloid leukemia (AML) patients with t(8;21)/ AML1-ETO or inv(16)/CBFb-MYH11 were distinguished from other AML patients by high and low expression of miR-126/126* (ref. 21) and let-7b/c, 20 respectively (Table 2).…”

CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia

“…miR-155 was reported to be upregulated in patients with an internal tandem duplication of the FLT3 gene (19). Schotte et al showed that 14 miRNAs are upregulated (miR-128a, miR-142-3p, miR-142-5p, miR-150, miR181a, miR-181b, miR-181c, miR-193a, miR-196b, miR-30e-5p, miR-34b, miR-365, miR-582, and miR-708), and 5 downregulated (miR-100, miR-125b, miR-151-5p, miR-99a, and let-7e), in acute lymphoblastic leukemia cells compared with normal CD34 + cells (20). Upregulation of miR-181a and miR-335 has been observed in AML patients carrying CEBPA gene mutations (21,22).…”