MicroRNA characterize genetic diversity and drug resistance in pediatric acute lymphoblastic leukemia - PubMed (original) (raw)

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

Diana Schotte et al. Haematologica. 2011 May.

Erratum in

Abstract

Background: MicroRNA 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 methods: Expression 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.

Results: All 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 B-cell 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 (P(FDR)<0.0001). Resistance to vincristine and daunorubicin was characterized by an approximately 20-fold up-regulation of miR-125b, miR-99a and miR-100 (P(FDR)≤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).

Conclusions: Genetic 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.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.

Clustering of ALL subtypes and normal hematopoietic control cells by expression levels of 325 miRNA. Hierarchical clustering of ALL patients, normal bone marrow samples, CD34+ selected cells and thymocytes by expression levels of 325 (unselected) miRNA. Heatmap shows which miRNA are overex-pressed (in red) and which are underexpressed (in green) relative to snoRNA input control. Expression levels are plotted as standardized Z-scores per miRNA.

Figure 2.

Figure 2.

Discriminative expression of miR-125b, miR-99a and miR-100 between drug-sensitive and -resistant precursor B-ALL patients. Expression levels relative to snoRNA are shown for miR-125b (A), miR-99a (B) and miR-100 (C). Dots represent individual samples of CD34+ selected cells (n=4), normal bone marrow samples ( =7) and the following precursor B-ALL patients: vincristine-sensitive (n=31; VCR/sens) and -resistant (n=30; VCR/resist) or daunorubicin-sensitive (n=29; DNR/sens) and -resistant (n=29; DNR/resist). Lines indicate median expression level in each group. The indicated P value is corrected for multiple-testing (FDR-corrected P value).

Figure 3.

Figure 3.

Prognostic value of a miRNA expression profile in newly diagnosed pediatric ALL. Kaplan-Meier estimates for the probability of disease-free survival of a miRNA expression profile are shown. This profile comprises the combined score of 14 miRNA which were, independently of subtype, predictive for the clinical outcome of newly diagnosed pediatric ALL cases (see Table 3). See Design and Methods section for details on how this profile was generated. Basically, patients were assigned a score of 1 if the expression level of a given miRNA was associated with a good prognosis and patients were assigned a score 2 if this expression level was associated with a poor prognosis. Next, the sum of individual scores of 14 miRNA was taken which resulted in a minimum score of 14 and a maximum score of 28. Patients were divided in two groups based on the median score (of 21) in 78 patients and Kaplan-Meier estimates were calculated. _P_=0.001, Cox proportional hazard analysis.

Similar articles

Cited by

References

    1. Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19(1):92–105. - PMC - PubMed
    1. Winter J, Jung S, Keller S, Gregory RI, Diederichs S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol. 2009;11(3):228–34. - PubMed
    1. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33. - PMC - PubMed
    1. Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303 (5654):83–6. - PubMed
    1. Zhang J, Jima DD, Jacobs C, Fischer R, Gottwein E, Huang G, et al. Patterns of microRNA expression characterize stages of human B-cell differentiation. Blood. 2009;113(19):4586–94. - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources