RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia
Authors
Choi, AHyunIllendula, Anuradha
Pulikkan, John A.
Roderick, Justine E.
Tesell, Jessica M.
Yu, Jun
Hermance, Nicole M.
Zhu, Lihua (Julie)
Castilla, Lucio H.
Bushweller, John H.
Kelliher, Michelle A.
Document Type
Journal ArticlePublication Date
2017-10-12
Metadata
Show full item recordAbstract
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.Source
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 siteDOI
10.1182/blood-2017-03-775536Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36638PubMed ID
28790107Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1182/blood-2017-03-775536