1. ¹Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA
2. ²Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA
3. ³Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA
4. ⁴Microarray and Bioinformatics Facility Core, Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, USA
5. ⁵Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA

Correspondence: Dr JW Taub, Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Department of Pediatrics, Wayne State University School of Medicine, 3901 Beaubien Boulevard, Detroit, MI 48201, USA. E-mail: jtaub@med.wayne.edu

Received 28 September 2007; Revised 7 November 2007; Accepted 16 November 2007; Published online 20 December 2007.

Abstract

Acute myeloid leukemia (AML) in Down syndrome (DS) children has several unique features including a predominance of the acute megakaryocytic leukemia (AMkL) phenotype, higher event-free survivals compared to non-DS children using cytosine arabinoside (ara-C)/anthracycline-based protocols and a uniform presence of somatic mutations in the X-linked transcription factor gene, GATA1. Several chromosome 21-localized transcription factor oncogenes including ETS2 may contribute to the unique features of DS AMkL. ETS2 transcripts measured by real-time RT–PCR were 1.8- and 4.1-fold, respectively, higher in DS and non-DS megakaryoblasts than those in non-DS myeloblasts. In a doxycycline-inducible erythroleukemia cell line, K562pTet-on/ETS2, induction of ETS2 resulted in an erythroid to megakaryocytic phenotypic switch independent of GATA1 levels. Microarray analysis of doxycycline-induced and doxycycline-uninduced cells revealed an upregulation by ETS2 of cytokines (for example, interleukin 1 and CSF2) and transcription factors (for example, TAL1), which are key regulators of megakaryocytic differentiation. In the K562pTet-on/ETS2 cells, ETS2 induction conferred differences in sensitivities to ara-C and daunorubicin, depending on GATA1 levels. These results suggest that ETS2 expression is linked to the biology of AMkL in both DS and non-DS children, and that ETS2 acts by regulating expression of hematopoietic lineage and transcription factor genes involved in erythropoiesis and megakaryopoiesis, and in chemotherapy sensitivities.