RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia. Blood 2017 Oct 12;130(15):1722-1733
Date
08/10/2017Pubmed ID
28790107Pubmed Central ID
PMC5639483DOI
10.1182/blood-2017-03-775536Scopus ID
2-s2.0-85031292142 (requires institutional sign-in at Scopus site) 64 CitationsAbstract
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-CreERT2Runx1f/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 CBFβ 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.
Author List
Choi A, Illendula A, Pulikkan JA, Roderick JE, Tesell J, Yu J, Hermance N, Zhu LJ, Castilla LH, Bushweller JH, Kelliher MAAuthor
John A. Pulikkan PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Basic Helix-Loop-Helix Transcription Factors
Cell Line, Transformed
Cell Line, Tumor
Cell Proliferation
Cell Survival
Chromatin
Core Binding Factor Alpha 2 Subunit
Core Binding Factor beta Subunit
Enhancer Elements, Genetic
Gene Deletion
Gene Expression Regulation, Leukemic
Humans
Mice
Oncogenes
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Protein Binding
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-myb
Proto-Oncogene Proteins c-myc
Receptors, Notch
T-Cell Acute Lymphocytic Leukemia Protein 1
