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Acute Leukemias

The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy

Leukemia volume 22, pages 521–529 (2008)Cite this article

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.

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Acknowledgements

We thank the Children's Oncology Group AML Biology Subcommittee for providing the clinical specimens that made this study possible. This study is dedicated in memory of Charles O’Brien for his longstanding support of childhood cancer research. The study is supported by grants (RO1 CA92308 and RO1 CA120772) from the National Cancer Institute, the Leukemia and Lymphoma Society, Leukemia Research Life, BPCT Golf Charity, The Elana Fund, Justin's Gift Charity, the Dale Meyer Endowment for Leukemia Research, The Ryan Gibson Foundation and The Ring Screw Textron Chair in Pediatric Cancer Research. Microarray data analysis was supported by the Microarray and Bioinformatics Facility Core, Wayne State University, NIEHS Center Grant P30 ES06639. JWT is a Scholar in Clinical Research of the Leukemia and Lymphoma Society. YG is a recipient of a Research Award from the Children's Leukemia Foundation of Michigan and a Research Award from the Children's Research Center of Michigan. SP was supported by T32 CA009531.

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Authors and Affiliations

  1. Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA

    Y Ge, K M LaFiura, Q Chen, S G Payton, L H Matherly & J W Taub

  2. Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA

    Y Ge & J W Taub

  3. Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA

    Y Ge, S G Payton & L H Matherly

  4. Microarray and Bioinformatics Facility Core, Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, USA

    A A Dombkowski, S Salagrama & A E Diakiw

  5. Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA

    S A Buck & J W Taub

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Ge, Y., LaFiura, K., Dombkowski, A. et al. The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy. Leukemia 22, 521–529 (2008). https://doi.org/10.1038/sj.leu.2405066

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