ETO2 Regulates Cell-Fate Genes and Controls Relapse in Acute Myeloid Leukemia

Abstract

The cell-fate of hematopoietic stem cells (HSCs) and their malignant version, leukemia stem cells (LSCs), are controlled by antagonistic functions of two classes of genes. We defined these genes as pro-HSC/LSC and anti-HSC/LSC genes based on their abilities to increase or decrease the steady state numbers of stem cells. Expansion of LSCs is thought to be an early step towards relapse (Lapidot, Sirard et al. 1994, Huntly and Gilliland 2005, Vasanthakumar and Godley 2014), a medical condition with no effective cures. We show here that the expression of both pro- and anti-HSC/LSC genes are coordinately controlled by ETO2, a transcriptional corepressor of E-protein family of transcription factors (Zhang, Kalkum et al. 2004, Gow, Guo et al. 2014). In both HSCs and acute myeloid leukemia (AML) cells, ETO2 occupies active chromatin regions that encompass enhancers and promoters of pro- and anti-HSC/LSC genes. ETO2 orchestrates the binding of epigenetic modifiers and transcription factors to enhance the expression of self-renewal and survival genes while reducing the expression of growth arrest and pro-inflammatory genes. Further supporting a role of ETO2 in maintaining the self-renewable population of HSCs and LSCs, depleting ETO2 compromises self-renewal of HSCs and diminishes in vivo propagation of AML cells.Analysis of multiple patient datasets supports the conclusion that relapse requires a threshold level of ETO2 expression. Attaining this threshold level requires a conserved gene activation mechanism mediated by GCN5 histone acetyltransferase. Inhibiting GCN5 reduces ETO2 and abolishes colony-formation capacity of primary AML cells. We also show that the conserved and diverged functions between ETO2 and AML1-ETO, a leukemia fusion protein expressed in t(8;21) AML, combined with a newly-discovered ability of AML1-ETO to repress ETO2 transcription, defines the unique properties of t(8;21) AML and explains its long-observed favorable prognosis. Importantly, we show that despite an enriched expression of HSC/LSC genes, relapse is paused in t(8;21) AML due to AML1-ETO-mediated downregulation of ETO2 and requires overcoming this repression to proceed. Thus, targeting GCN5/ETO2 axis to achieve a similar effect as that imposed by AML1-ETO is expected to dramatically improve therapeutic efficacy of AML, whose current survival rate is worse than most cancers and leukemias (Supported by NIH grants R01HL093195-01A1 and R21CA178513 to JZ and T32 training grant T32GM008306-26A1 to NS).Gow, C. H., C. Guo, D. Wang, Q. Hu and J. Zhang (2014). “Differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways.” Nucleic Acids Res 42(1): 137-152.Huntly, B. J. and D. G. Gilliland (2005). “Leukaemia stem cells and the evolution of cancer-stem-cell research.” Nat Rev Cancer 5(4): 311-321.Lapidot, T., C. Sirard, J. Vormoor, B. Murdoch, T. Hoang, J. Caceres-Cortes, M. Minden, B. Paterson, M. A. Caligiuri and J. E. Dick (1994). “A cell initiating human acute myeloid leukaemia after transplantation into SCID mice.” Nature 367(6464): 645-648.Vasanthakumar, A. and L. A. Godley (2014). “On the origin of leukemic species.” Cell Stem Cell 14(4): 421-422.Zhang, J., M. Kalkum, S. Yamamura, B. T. Chait and R. G. Roeder (2004). “E protein silencing by the leukemogenic AML1-ETO fusion protein.” Science 305(5688): 1286-1289. DisclosuresNo relevant conflicts of interest to declare.