The prognostic and functional role of microRNAs in acute myeloid leukemia

Abstract

IntroductionMicroRNAs are naturally occurring 18-to 25-nucleotide RNAs that are cleaved from 70-to 100-nucleotide hairpin precursors by a complex protein system that includes the RNase III Drosha and Dicer, members of the Argonaute family. 1,2 Mature microRNAs typically hybridize to the 3Ј-untranslated regions of protein-coding messenger RNAs (mRNAs) and cause their post-transcriptional repression and/or degradation in proliferating cells, 1,2 although emerging data indicate that microRNAs can also regulate gene expression through binding to "seedless" 3Ј-untranslated region microRNA recognition elements 3 or increase translation of target mRNAs on cell cycle arrest. 4 MicroRNAs, whose nomenclature is described by Griffiths-Jones et al, 5 regulate normal cell homeostasis and are involved in many physiologic processes, including hematopoiesis. [6][7][8] Recently, dysregulation of microRNAs has been shown in many types of solid tumors and leukemia. 9 Direct involvement of microRNAs in cancer has been suggested by a study demonstrating that several microRNAs are localized in genomic regions associated with cancer, such as breakpoint regions in chromosome aberrations involving oncogenes or tumor suppressor genes, minimal regions of loss of heterozygosity, minimal regions of amplification, and at loci close to fragile sites and integration sites of the human papilloma virus. 10 Supporting their role in carcinogenesis, microRNAs mapped to the chromosomal regions deleted in cancer samples were found expressed at low levels, 9 and several functional studies confirmed the important role of microRNA deregulation in hematologic malignancies, including acute myeloid leukemia (AML). 9,[11][12][13][14][15][16][17][18][19] Patterns of microRNA expression differ between normal cells and AML blastsProfiling and functional experiments revealed that several microRNAs play a role in the regulation of hematopoiesis. [6][7][8] Hence, it was not surprising that many microRNAs are differentially expressed between AML blasts and normal cells. [20][21][22][23] However, microRNA signatures derived by comparing microRNA expression between normal and malignant cells have shared few similarities among different studies. This lack of uniformity could be explained by the use of normal CD34 ϩ cells obtained under different conditions, such as after growth factor mobilization versus collected directly from the bone marrow (BM) with no mobilization. It is possible that the use of growth factors could change microRNA expression in CD34 ϩ cells because similar changes have been observed for mRNA expression. 24 In addition, some studies used unselected BM mononuclear cells from healthy donors instead of CD34 ϩ cells as controls. 20 The use of different platforms for microRNA profiling and differences in the frequency of cytogenetic and/or molecular genetic alterations, shown to affect microRNA expression (see "Correlations of microRNA expression with cytogenetics in AML" and "Correlations of microRNA expression with molecular markers in CN-AML"), ...

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

“…There is accumulating evidence that dysregulation of miRNA expression is involved in various cancers, including hematological malignancies (31)(32)(33)(34). Here, we identified for the first time a CXCR4/let-7a/BCL-XL axis in human AML cells that may be responsible for the chemoresistance observed in the clinical setting.…”

Complex oncogene dependence in microRNA-125a–induced myeloproliferative neoplasms

“…Alteration in miRNA gene expression or function can promote cancer initiation and progression in vivo, leading to the recognition that this class of small noncoding RNAs can function as both oncogenes and tumor suppressors (3)(4)(5). Much less is known, however, regarding the role of miRNAs in cancer maintenance.…”

Quantification of microRNA-181b in Egyptian Acute Myeloid Leukemia Patients and its Relation to Prognosis

“…Activation of Toll-like receptors induces production of inflammatory cytokines which promote the survival and proliferation of AML blasts. These genes are down regulated by miR-181 family [16] .…”

“…Additionally, molecular studies on cytogenetically normal AML patients (CN-AML) showed that CEBPA mutations, which carry favorable prognostic value in CN-AML, have been associated with an upregulation of members of miR-181 family [16] . They integrated gene expression with miRNA expression profile and observed a functional relationship between them.…”