MicroRNAs: new players in acute myeloid leukaemia

British Journal of Cancer (2009) 101, 743 – 748 & 2009 Cancer Research UK All rights reserved 0007 – 0920/09 $32.00 www.bjcancer.com Minireview MicroRNAs: new players in acute myeloid leukaemia V Havelange1,2, R Garzon3 and CM Croce*,1 1 Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA; Hematological Section, The Human Genetic Center, Université catholique de Louvain, Brussels, Belgium; 3Division of Hematology and Oncology, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA 2 MicroRNAs (miRNAs) are short non-coding RNAs that have key functions in a wide array of critical cell processes, including haematopoiesis by regulating the expression of multiple genes. Aberrant miRNA expression has been described in acute myeloid leukaemia suggesting a role in leukaemogenesis. In this review we summarise the current knowledge. British Journal of Cancer (2009) 101, 743 – 748. doi:10.1038/sj.bjc.6605232 www.bjcancer.com Published online 11 August 2009 & 2009 Cancer Research UK Keywords: microRNAs; acute myeloid leukaemia; miRNA profiling; molecular alterations Acute myeloid leukaemia (AML) arises from myeloid progenitor cells that are arrested at early stages of differentiation. It is a cytogenetically heterogeneous disorder with acquired recurrent chromosomal alterations detected in about 55% of adult patients, such as translocations (i.e. t(15;17); t(8;21); t(9;11)), inversions (i.e. inv(16)), deletions (i.e. del(7q)), trisomies (i.e. þ 8) and monosomies (i.e. 5/7) (reviewed by Mrózek et al, 2004). Importantly, AML patients could be stratified according to the detected cytogenetic abnormalities in high-, intermediate- and low-risk cytogenetic groups (Mrózek et al, 2004). In the remaining 45% of cases of cytogenetically normal AML (CN-AML), a number of novel molecular abnormalities have been described, such as the internal tandem duplication (ITD) in the juxtamembrane domain or mutation in the second tyrosine kinase domain (TKD) of FMSlike tyrosine kinase 3 (FLT3) gene, mutations in the nucleophosmin (NPM1) gene, CCAAT/enhancer binding protein-a (CEBPA) gene and in the Wilms’ tumour gene and partial tandem duplication (PTD) of the mixed-lineage leukaemia (MLL) gene (reviewed by Mrózek et al, 2007). In addition to mutations, overexpression of ERG (v-ets erythroblastosis virus E26 oncogene homologue) and BAALC (brain and acute leukaemia, cytoplasmic) genes has been found in CN-AML (Tanner et al, 2001; Baldus et al, 2004). Like cytogenetics, molecular abnormalities in CN-AML not only have improved the classification of this now heterogeneous group of AMLs, but also have prognostic implications. For example, NPM1 mutations predict favourable outcome in young CN-AML in the absence of FLT3-ITD (reviewed by Mrózek et al, 2007). The presence of CEBPA mutations identifies a group of patients with a better prognosis within the young high-risk CN-AML group (patients with FLT3-ITD and/or wild-type (wt) NPM1) (Marcucci et al, 2008b). Otherwise, CN-AML patients with FLT3ITD have a significantly inferior outcome compared to patients *Correspondence: Dr CM Croce, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Biomedical Research Tower, Room 1084, 460 West 12th Avenue, Columbus, OH 43210, USA; E-mail: Received 7 April 2009; revised 29 June 2009; accepted 13 July 2009; published online 11 August 2009 with FLT3-wt (reviewed by Mrózek et al, 2007). The level of FLT3-ITD mutant allele was also correlated with outcome, whereas the prognosis impact of FLT3-TKD is controversial. MLL-PTD has been associated with shorter complete remission duration or worse event-free survival (EFS) without effect on overall survival (reviewed by Mrózek et al, 2007). Many of these prognostic studies are difficult to interpret because of the coexistence of one or two mutations which have to be taken in consideration because of their probable interactions and influence on prognosis. Additional limitations arise from the low number of patients and treatment differences (reviewed by Gaidzik and Döhner, 2008). Despite great progress, AML biology remained poorly understood. Over the past years, complementary DNA (cDNA) microarrays have been used to interrogate whole gene expression in AML samples. Indeed, several groups have reported distinctive signatures associated with particular cytogenetic and molecular groups of AML (Bullinger et al, 2004; Ross et al, 2004; Valk et al, 2004; Radmacher et al, 2006). Using unsupervised analyses, we identified novel subgroups of AMLs based on gene expression profiling (GEP) obtained using Affymetrix microarrays. Moreover GEP allowed to further classify previously defined cytogenetic subgroups. For example, GEP uncovered substantial heterogeneity in core binding factor (CBF) AMLs suggesting alternative mutations or deregulated pathways involved in transformation (Bullinger et al, 2007). In some cases, the GEP signatures were able to predict outcome (Bullinger et al, 2004; Ross et al, 2004; Valk et al, 2004). More importantly, a cDNA microarray study identified a gene expression signature that separated CN-AML into two prognostically relevant subgroups (Bullinger et al, 2004). The prognostic value of this signature was validated in a different set of CN-AML patients using a different microarray platform (Radmacher et al, 2006). These studies confirmed the possible applicability of GEP for outcome prediction in CN-AML. Despite this progress, focusing on known genes will likely not suffice to uncover the molecular puzzle of AML. The integration of a whole genome approach including non-coding RNAs may lead to an improved understanding of AML biology. MicroRNAs (miRNAs) are non-coding RNAs of 19 – 25 nucleotides in length that regulate gene expression by repressing MicroRNAs: news actors in acute myeloid leukaemia V Havelange et al 744 translation or accelerating mRNA decay (Bartel, 2004). MicroRNAs are involved in critical biological processes, including development, cell differentiation, apoptosis, proliferation and haematopoiesis (Chen et al, 2004; Poy et al, 2004; Xu et al, 2004; Cheng et al, 2005; Karp and Ambros, 2005). Recent data indicate that miRNAs are deregulated in diseases, such as diabetes, heart disease and cancer (Calin et al, 2002; Poy et al, 2004; van Rooij et al, 2006). The first study connecting miRNAs and leukaemia reported frequent down-regulation of the miRNA cluster; miR-15a/miR-16-1 in chronic lymphocytic leukaemia (CLL) (Calin et al, 2002). This cluster is localised at chromosome 13q14.3, a genomic region, which is deleted in about 65% of CLL patients. Further work showed that miR-15a/miR-16-1 cluster targets the anti-apoptotic BCL-2 (Cimmino et al, 2005). Thereby, this study provides with an alternative explanation for the BCL-2 (...truncated)