RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia
Department of Molecular, Cell and Cancer Biology; UMass Metabolic Network
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
The gene encoding the RUNX1 transcription factor is mutated in a subset of T-cell acute lymphoblastic leukemia (T-ALL) patients, and RUNX1 mutations are associated with a poor prognosis. These mutations cluster in the DNA-binding Runt domain and are thought to represent loss-of-function mutations, indicating that RUNX1 suppresses T-cell transformation. RUNX1 has been proposed to have tumor suppressor roles in T-cell leukemia homeobox 1/3-transformed human T-ALL cell lines and NOTCH1 T-ALL mouse models. Yet, retroviral insertional mutagenesis screens identify RUNX genes as collaborating oncogenes in MYC-driven leukemia mouse models. To elucidate RUNX1 function(s) in leukemogenesis, we generated Tal1/Lmo2/Rosa26-CreER(T2)Runx1(f/f) mice and examined leukemia progression in the presence of vehicle or tamoxifen. We found that Runx1 deletion inhibits mouse leukemic growth in vivo and that RUNX silencing in human T-ALL cells triggers apoptosis. We demonstrate that a small molecule inhibitor, designed to interfere with CBFbeta binding to RUNX proteins, impairs the growth of human T-ALL cell lines and primary patient samples. We demonstrate that a RUNX1 deficiency alters the expression of a crucial subset of TAL1- and NOTCH1-regulated genes, including the MYB and MYC oncogenes, respectively. These studies provide genetic and pharmacologic evidence that RUNX1 has oncogenic roles and reveal RUNX1 as a novel therapeutic target in T-ALL.
DOI of Published Version
Blood. 2017 Oct 12;130(15):1722-1733. doi: 10.1182/blood-2017-03-775536. Epub 2017 Aug 8. Link to article on publisher's site
Choi A, Illendula A, Pulikkan JA, Roderick JE, Tesell JM, Yu J, Hermance NM, Zhu L(, Castilla LH, Bushweller JH, Kelliher MA. (2017). RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia. UMass Metabolic Network Publications. https://doi.org/10.1182/blood-2017-03-775536. Retrieved from https://escholarship.umassmed.edu/metnet_pubs/157