Gene expression profiles in acute myeloid leukemia with common translocations using SAGE

Abstract

Identification of the specific cytogenetic abnormality is one of the critical steps for classification of acute myeloblastic leukemia (AML) which influences the selection of appropriate therapy and provides information about disease prognosis. However at present, the genetic complexity of AML is only partially understood. To obtain a comprehensive, unbiased, quantitative measure, we performed serial analysis of gene expression (SAGE) on CD15 ؉ myeloid progenitor cells from 22 AML patients who had four of the most common translocations, namely t(8;21), t(15;17), t(9;11), and inv(16). The quantitative data provide clear evidence that the major change in all these translocation-carrying leukemias is a decrease in expression of the majority of transcripts compared with normal CD15 ؉ cells. From a total of 1,247,535 SAGE tags, we identified 2,604 transcripts whose expression was significantly altered in these leukemias compared with normal myeloid progenitor cells. The gene ontology of the 1,110 transcripts that matched known genes revealed that each translocation had a uniquely altered profile in various functional categories including regulation of transcription, cell cycle, protein synthesis, and apoptosis. Our global analysis of gene expression of common translocations in AML can focus attention on the function of the genes with altered expression for future biological studies as well as highlight genes͞pathways for more specifically targeted therapy.hematopoietic cell differention ͉ diagnostic microarray T he pathogenesis of acute myeloid leukemia (AML) in many patients is linked to oncogenic fusion proteins, generated as a consequence of chromosome translocations or inversions (1). Many different translocations have been described in AML, the most frequent being the t(9;11), t(15;17), t(8;21), and inv(16), which, taken together with their variants, account for Ϸ20-30% of AML cases (2, 3), although a recent analysis by Mitelman et al. (4) suggests that the proportion may be closer to 10%. These recurring translocations are now the basis for classification of some patients with AML. Despite genetic heterogeneity, there is increasing evidence for some common molecular and biological mechanisms in the genesis of AML. In particular, one of the components of each fusion protein is almost invariably a transcription factor, frequently involved in the regulation of myeloid cell differentiation (5). As a consequence, AML-associated fusion proteins function as aberrant transcriptional regulators with the potential to interfere with the normal processes of myeloid cell differentiation.Genome-wide gene expression profiling is becoming useful for the classification of many types of cancer (6, 7), including AML and acute lymphoblastic leukemia (8-15). Although AML subtypes can be distinguished by oligonucleotide microarrays, the results of analysis of different translocations between laboratories are not always similar. This lack of consistency has probably resulted from the heterogeneous nature of clinical samples (age, se...

The multi-functional cellular adhesion molecule CD44 is regulated by the 8;21 chromosomal translocation

“…Specifically, Sparc is known to block solid tumor growth 33 and has recently been demonstrated to be decreased in myeloid/lymphoid or mixed-lineage leukemia (MLL) rearranged and t(8;21)-associated AML. 34,35 Furthermore, Igfbp7 was increased in the t(8;21) Kasumi-1 cell line following siRNA treatment against AML1-ETO, thus suggesting that it is also a potential direct target of AML1-ETO 36 or in our case AML1-ETO9a. Flow cytometric analysis of the mouse hematopoietic stem cell marker Sca-1, which showed a 8.5-fold increase in the microarray, displayed an increase in the expression of Sca-1 on the AML1-ETO9a FDCP-mix A4-expressing cells (Figure 2b).…”

“…Sparc was also decreased in t(8;21) patient samples. 34,35 The other secreted protein Igfbp7 is a major factor upregulated during U937 differentiation by vitamin D3 treatment, as the cells undergo growth arrest. 44 A decrease in Igfbp7 is also associated with tumorigenesis in an in vivo mouse tumor model.…”

Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML

“…Expression of 1045 genes were dysregulated Ն 1.5-fold in AE9a LK cells, with 337 up-regulated and 486 down-regulated by at least 2-fold (P Ͻ .001, 2-sample t test; supplemental Table 1). Among these genes, 195 were also found to be dysregulated in AML1-ETO-transduced human hematopoietic cells [30][31][32] or t(8;21) AML blasts 33,34 (supplemental Table 2). Among the up-regulated genes are positive cell-cycle regulators, such as Ccnb1, Ccnd2, and Cdc25b.…”

A comparison of gene expression profiles between primary human AML cells and AML cell line

“…SAGE tags were extracted from the sequences using SAGE 2000 software. Acquisition of the primary human t(9;11) cells SAGE data For the comparison with MM6, the SAGE data of primary human t(9;11) cells were obtained from the paper published by Lee et al (2006). The data of three t(9;11) AML-M5/5a (FAB classification) cells were integrated and extracted randomly to make one expression profile.…”

“…Mono Mac 6 cells and the primary human t(9;11) cells To examine whether the pattern of gene expression of the Mono Mac 6 cell line is different from that of primary cells from bone marrow samples with t(9;11) AML patients (the SAGE tags data were from Lee et al, 2006), the SAGE tags from both cells were compared via statistical and bioinformatical analysis. Among the 884 unique SAGE tag obtained from the analysis, p values < 0.05 and 4-fold expression change, 693 (78%) tags were increased in MM6 cells and 191 (22%) were decreased.…”