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


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.
Erasmus MC-Sophia Children's Hospital, Dept. of Pediatric Oncology and Hematology, room Sp2456 P.O. Box 2060, 3000 CB Rotterdam, the Netherlands.
Diana
D
Schotte
Renée X
RX
De Menezes
Farhad
F
Akbari Moqadam
Leila Mohammadi
LM
Khankahdani
Ellen
E
Lange-Turenhout
Caifu
C
Chen
Rob
R
Pieters
Monique L
ML
Den Boer
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001215:Asparaginase / Q000627:therapeutic use; D002648:Child; D016000:Cluster Analysis; D003630:Daunorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020869:Gene Expression Profiling; D014644:Genetic Variation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D011379:Prognosis; D014750:Vincristine / Q000627:therapeutic use
D000970:Antineoplastic Agents; D035683:MicroRNAs; D014750:Vincristine; D001215:Asparaginase; D003630:Daunorubicin
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