Expression data from RDI treated T-ALL cells

ABSTRACT: RUNX1 and CBFB, which encode subunits of the core binding factor, are frequent targets of chromosomal aberrations in hematological malignancies. We previously determined that CBFβ (encoded by CBFB) is important for the transforming activity of the chimeric protein AML1-ETO (RUNX1-RUNX1T1) generated by the t(8;21), and other studies showed that normal Runx1 functions are essential for survival and maintenance of some leukemias lacking RUNX1 or CBFB mutations. Thus, we hypothesized that we could achieve therapeutic efficacy in multiple leukemias by targeting the Runx1:CBFβ interaction with small molecule inhibitors. Using the structure of the DNA binding Runt domain (RD) of Runx1 and its interface with CBFβ, we employed a computational screen of a library of 78,000 drug-like compounds, and further optimized our initial hits. The Runt domain inhibitors (RDIs) bind directly to the RD and disrupt its interaction with CBFβ. These tool compounds reduced growth and induced apoptosis of t(8;21) acute myeloid leukemia (AML) cell lines, and reduced the progenitor activity of mouse and human leukemia cells harboring the t(8;21), but not normal bone marrow cells. The RDIs had similar effects on murine and human T cell acute lymphocytic leukemia (T-ALL) cell lines that did not harbor the t(8;21) A murine T-ALL cell line 720, derived from Tcf12+/- mouse expressing a Tal1 transgene under the control of the Lck promoter, was especially sensitive to the inhibitors. To gain a better understanding of the mechanism of action of the Runt Domain Inhibitors (RDIs) we performed global gene expression analysis of the highly responsive 720 T-ALL cells following treatment. 720 T-ALL cells were treated with RDIs and harvested 8 hours later, before they underwent apoptosis, and expression was analyzed using microarrays. 720 T-ALL cells were cultured in the presence of Runt Domain Inhibitors for 8 hours, total RNA was then purified and gene expression was analyzed by microarray.

ORGANISM(S): Mus musculus

SUBMITTER: Nancy Speck 

PROVIDER: E-GEOD-70495 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress