Differential expression of specific microRNA and their targets in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) the most common acute leukemia in adults is characterized by various cytogenetic and molecular abnormalities. However, the genetic etiology of the disease is not yet fully understood. MicroRNAs (miRNA) are small noncoding RNAs which regulate the expression of target mRNAs both at transcriptional and translational level. In recent years, miRNAs have been identified as a novel mechanism in gene regulation, which show variable expression during myeloid differentiation. We studied miRNA expression of leukemic blasts of 29 cases of newly diagnosed and genetically defined AML using quantitative reverse transcription polymerase chain reaction (RT-PCR) for 365 human miRNA. We showed that miRNA expression profiling reveals distinctive miRNA signatures that correlate with cytogenetic and molecular subtypes of AML. Specific miRNAs with consolidated role on cell proliferation and differentiation such as miR-155, miR-221, let-7, miR-126 and miR-196b appear to be associated with particular subtypes. We observed a significant differentially expressed miRNA profile that characterizes two subgroups of AML with different mechanism of leukemogenesis: core binding factor (CBF) and cytogenetically normal AML with mutations in the genes of NPM1 and FLT3-ITD. We demonstrated, for the first time, the inverse correlation of expression levels between miRNA and their targets in specific AML genetic groups. We suggest that miRNA deregulation may act as complementary hit in the multisteps mechanism of leukemogenesis offering new therapeutic strategies. Am. J. Hematol. 85:331-339, 2010. V

MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output

“…In the case of miR-125b, it will also be of interest to assess whether it transforms HSCs or a committed myeloid progenitor and to characterize secondary mutations that may assist in this process. Many of the miRNAs identified in our study, including miR125b, miR-155, miR-126, miR-196b, and miR-99a, have been shown to be dysregulated in different subsets of AML (31). Because we have shown functional relevance for many of these HSC miRNAs in vivo, including the abilities of miR-155 (16) and now miR-125b to trigger aggressive MPDs and myeloid leukemia, respectively, therapeutic targeting of this subset may be effective in combating hematopoietic cancers.…”

MiR-125 in normal and malignant hematopoiesis

“…25 These results suggest that the miR-125b-2 polycistron may be regulated by posttranscriptional mechanisms in early hematopoiesis. Similar to miR-125b-2, miR-99a was found to be upregulated in AMKL cell lines, 61 in AMLs with the translocation AML1/ETO, 41 in APL involving PML/RARA 44 and in resistant ALLs. 49 However, in more differentiated B-cells, a correlation in the expression level could not be demonstrated between miR-125b-2 and miR-99a or let-7c.…”

“…The expression levels varied depending on the methodologies used for expression and controls, but are generally up to 20-fold compared with normal BM. These malignancies include myelodysplastic syndrome involving the del (5q), 39,40 AMLs harboring the AML1/ETO translocation, 41 AMLs associated with the FLT3 mutation, 41 a few cases of chronic myelogenous leukemia, myeoproliferative neoplasms 42 and acute promyelocytic leukemia 43,44 (Table 1). The most investigated hematopoietic malignancy with increased expression of miR-125b is acute megakaryocytic leukemia associated with Down's syndrome (DS).…”

Deregulation of microRNAs in myelodysplastic syndrome

“…30,31 Others have correlated miRNA expression changes with leukemia subtype, cytogenetic profile and molecular alterations. 30,[32][33][34] …”