期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 36, 页码 14592-14597出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1200037109
关键词
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资金
- National Institutes of Health (NIH) [X01 MH083259-01, CA140188, AG031300]
- Molecular Libraries Initiative of the NIH Roadmap for Medical Research
- Intramural Research Program of NHGRI, NIH [CA140188, AG031300]
- Johns Hopkins-National Cancer Institute Pediatric Hematology/Oncology Fellowship
- NIH
Core binding factor (CBF) leukemias, those with translocations or inversions that affect transcription factor genes RUNX1 or CBFB, account for similar to 24% of adult acute myeloid leukemia (AML) and 25% of pediatric acute lymphocytic leukemia (ALL). Current treatments for CBF leukemias are associated with significant morbidity and mortality, with a 5-y survival rate of similar to 50%. We hypothesize that the interaction between RUNX1 and CBF beta is critical for CBF leukemia and can be targeted for drug development. We developed high-throughput AlphaScreen and time-resolved fluorescence resonance energy transfer (TR-FRET) methods to quantify the RUNX1-CBF beta interaction and screen a library collection of 243,398 compounds. Ro5-3335, a benzodiazepine identified from the screen, was able to interact with RUNX1 and CBF beta directly, repress RUNX1/CBFB-dependent transactivation in reporter assays, and repress runx1-dependent hematopoiesis in zebrafish embryos. Ro5-3335 preferentially killed human CBF leukemia cell lines, rescued preleukemic phenotype in a RUNX1-ETO transgenic zebrafish, and reduced leukemia burden in amouse CBFB-MYH11 leukemia model. Our data thus confirmed that RUNX1-CBF beta interaction can be targeted for leukemia treatment and we have identified a promising lead compound for this purpose.
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