A decade of genome-wide gene expression profiling in acute myeloid leukemia: flashback and prospects

Abstract

The past decade has shown a marked increase in the use of high-throughput assays in clinical research into human cancer, including acute myeloid leukemia (AML). In particular, genome-wide gene expression profiling (GEP) using DNA microarrays has been extensively used for improved understanding of the diagnosis, prognosis, and pathobiology of this heterogeneous disease. This review discusses the progress that has been made, places the technologic limitations in perspective, and highlights promising future avenues. (Blood. 2009;113:291-298) IntroductionAcute myeloid leukemia (AML) is characterized by a maturation block and accumulation of myeloid progenitor cells. 1,2 Clinically, it has been recognized as a heterogeneous disorder. 1,2 Laboratory support for that notion has come from various directions. Chromosomal abnormalities and gene mutations are common in AML, many of which are apparent in particular subtypes. 3,4 Classification of AML subtypes is clinically relevant, as particular abnormalities are associated with distinct clinical behavior. 1 For instance, recurring reciprocal translocations t(15;17)(q22;q21), t(8;21)(q22;q22), or inv(16)(p13q22)/t(16)16(p13;q22), further abbreviated as t(15;17), t(8;21), and inv(16), respectively, predict favorable prognosis, whereas other chromosomal aberrations are associated with inferior outcome. 1 Likewise, sequence mutations in certain genes are associated with either favorable or unfavorable response to treatment. 4 Insight into cytogenetic and genetic aberrations is invaluable for diagnosis, and it may also allow for better understanding of the pathobiology. Furthermore, it may enable the development and application of specific treatment modalities targeted to underlying oncogenic abnormalities. The efficacy of such drugs as all-trans retinoic acid for the treatment of t(15;17) AML and imatinib for BCR-ABL-positive chronic myeloid leukemia offer well established examples. 5 Despite great progress, much of the heterogeneity of AML remains to be resolved. A significant proportion of human AML appears cytogenetically and genetically normal, which implies that the underlying molecular abnormalities are still unknown. Furthermore, it is likely that in AMLs carrying recognizable aberrations additional hits await to be uncovered, as one lesion usually does not appear sufficient for full leukemic transformation. 6 In recent years, DNA microarrays, together with the availability of the complete nucleotide sequence of the human genome, have spurred the search for abnormalities in cancer, including AML. 7 The accessibility of these tools allows assessment of abnormalities and variations on a genome wide basis, covering various molecular levels. 8 Gene expression profiling (GEP) is one of these technologies, in which DNA microarrays containing cDNAs or oligonucleotide probes are used to simultaneously measure levels of many different mRNA transcripts. [7][8][9][10] In an early landmark study in 1999, Golub and colleagues were able to use GEP to discriminate a collection of AML...

Entinostat Prevents Leukemia Maintenance in a Collaborating Oncogene-Dependent Model of Cytogenetically Normal Acute Myeloid Leukemia

“…Microarray-based gene expression profiling, in particular, has identified novel disease subclasses at diagnosis [1][2][3][4][5]. The ability to sequence complete genomes at high resolution has resulted in the generation of disease-specific data silos.…”

Gene expression profiling in the leukemic stem cell-enriched CD34+ fraction identifies target genes that predict prognosis in normal karyotype AML

“…In recent years, a number of gene expression profiling (GEP) studies has been performed in order to improve the identification of known cytogenetic subgroups and to recognize new clusters of AML patients with distinct gene-expression signatures. [6][7][8][9][10][11] Most of these AML GEP studies have been performed using the total AML-mononuclear cell (MNC) fraction. [6][7][8][9] As cell lineage and differentiation stages affect gene expression-based clustering, 6,7,10 the differentially expressed genes associated with the differentiation stage might obscure more basic gene expression information related to tumor initiation and maintenance.…”

Gene expression profiling in MDS and AML: potential and future avenues

“…The first sections focus on AML and MDS studies in adults and children, and discuss how GEP has helped (i) to identify characteristic gene expression patterns in MDS/AML subclasses, with specific cytogenetic and/or molecular genetic aberrations (class prediction), (ii) to discover novel leukemia subclasses (class discovery) and (iii) to predict response to standard therapy in both MDS and adult as well as pediatric AML (outcome prediction). 6,7 The final sections review potential applications of GEP including the prediction of drug response, drug discovery and future integrative data analysis approaches that will not only allow a refined patient management, but also provide deeper insights into the molecular mechanisms underlying MDS and AML. …”