RESUMEN
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 CBFß 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.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Elementos de Facilitación Genéticos/genética , Oncogenes , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogénicas c-myb/genética , Proteínas Proto-Oncogénicas c-myc/genética , Animales , Apoptosis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Línea Celular Transformada , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Cromatina/metabolismo , Subunidad beta del Factor de Unión al Sitio Principal/metabolismo , Eliminación de Gen , Regulación Leucémica de la Expresión Génica , Humanos , Ratones , Unión Proteica , Proteínas Proto-Oncogénicas/metabolismo , Receptores Notch/metabolismo , Proteína 1 de la Leucemia Linfocítica T AgudaRESUMEN
Although prognosis has improved for children with T-cell acute lymphoblastic leukemia (T-ALL), 20% to 30% of patients undergo induction failure (IF) or relapse. Leukemia-initiating cells (LICs) are hypothesized to be resistant to chemotherapy and to mediate relapse. We and others have shown that Notch1 directly regulates c-Myc, a known regulator of quiescence in stem and progenitor populations, leading us to examine whether c-Myc inhibition results in efficient targeting of T-ALL-initiating cells. We demonstrate that c-Myc suppression by small hairpin RNA or pharmacologic approaches prevents leukemia initiation in mice by eliminating LIC activity. Consistent with its anti-LIC activity in mice, treatment with the BET bromodomain BRD4 inhibitor JQ1 reduces C-MYC expression and inhibits the growth of relapsed and IF pediatric T-ALL samples in vitro. These findings demonstrate a critical role for c-Myc in LIC maintenance and provide evidence that MYC inhibition may be an effective therapy for relapsed/IF T-ALL patients.