MiRNA Profiles in Acute Lymphoblastic Leukemia: Rather a Characteristic for the Leukemia Subtype Than a Reflection of Its Differentiation Status.

MicroRNAs (miRNAs) are noncoding RNAs that regulate processes involved in proliferation and differentiation. Since abnormal proliferation and differentiation is the hallmark of cancer, miRNAs may have a role in the pathogenesis of cancer. Here we examined the miRNA expression in various subtypes of Childhood Acute Lymphoblastic Leukemia (ALL) including MLL-rearranged ALL (n = 16), T-ALL (n = 10) and precursor B-ALL patients positive for TEL-AML1 (n = 10), BCR-ABL (n = 10), E2A-PBX (n = 8) or hyperdiploidy (more than 50 chromosomes, n = 10) and other precursor B-ALL patients that are negative for all major genetic abnormalities in ALL (n = 19). We have found that miR-196b is highly expressed only in MLL-rearranged ALL and its expression level is ∼400 to 700-fold (P < 0.05) higher than the levels in all other precursor B-ALL subtypes and T-ALL cases. Moreover, all precursor B-ALL subtypes including TEL-AML1, BCR-ABL, E2A-PBX and hyperdiploid positive cases have a 250- to 6500- fold upregulation (P ≤0.01) of miR-708 compared to MLL-rearranged ALL and T-ALL patients. Interestingly, it is known that MLL-translocated ALL arises in an earlier stage of B-lineage development compared to other precursor B-ALL subtypes negative for MLL rearrangements, thus subtype-specific expression of miR-196b and miR-708 could reflect a difference in maturation status. However, miR-196b and miR-708 expression levels do not seem to correlate with the differentiation status of the leukemia cells based on the immunoglobulin (Ig) and T-cell receptor (TCR) rearrangements in case of precursor B-ALL and EGIL classification in case of T-ALL. Furthermore, miR-196b is located between the HOXA9 and HOXA10 genes, which are known to be upregulated in MLL-translocated patients. Here we find a positive correlation between miR-196b expression and HOXA9/HOXA10 expression within MLL- rearranged and T-ALL patients. Further research has to reveal whether high expression of miR-196b actively contributes to leukemogenesis like HOX genes or whether it is an epiphenomenon of HOXA upregulation in MLL-rearranged ALL patients. All together, our present study suggests that the expression level of miR-196b and miR-708 reflects differences between genetic subtypes rather than differences in differentiation status and emphasizes the need to further investigate the role of these miRNAs in leukemogenesis.