PI: Stephen D. Nimer, MD ABSTRACT The leukemogenic AML1-ETO fusion protein, generated by the t(8;21), is the most common fusion protein in acute myeloid leukemia (AML). It contains the N-terminus of AML1/RUNX1, a transcription factor (TF) required for the development of definitive hematopoiesis in mice, and nearly the entire ETO protein, generally thought to function by recruiting co-repressor complexes, thereby turning AML1-ETO into a repressor of transcription1. We have previously identified a variety of genes whose expression is increased by AML1-ETO, but the mechanisms underlying this effect are not known. We have now determined that AML1-ETO binds the """"""""histone"""""""" lysine acetyltransferase p300 via its NHR1 domain (aa 245-430), which leads to its acetylation at lysine 43 (K43) and lysine 24 (K24). Deletion of the NHR1 domain eliminates the ability of AML1-ETO to activate gene expression but not its ability to function as a repressor. Furthermore, the NHR1 domain is required for the self-renewal promoting properties of AML1- EO, but not its ability to block differentiation. Based on the ability of AML1-ETO to recruit p300, we have determined that acetylation at K43, is absolutely essential for its leukemia and self- renewal promoting properties in both mouse and human AML models. This suggests several potential therapeutic strategies that could target this subtype of AML, including the use of p300 inhibitors, or inhibitors that block the binding of bromodomain-containing proteins which can bind to acetyl-K43 in AML1-ETO. To define the importance of specific protein-protein interactions involving AML1-ETO in leukemogenesis and the clinical applicability of targeting its activation, we propose the following specific aims:
Aim1 : Define the effect of p300 inhibitors on AML1-ETO driven AML using mouse models, cord blood derived human CD34+ cell models, and primary t(8;21)+ AML patient samples.
Aim 2 : Determine the role that transcriptional regulatory proteins that bind to K43 acetylated AML1- ETO (e.g. TAF7 or TAF 250) play in AML1-ETO driven leukemogenesis using RNA interference approaches.
Aim 3 : Determine whether blocking the binding of p300 or the critical transcriptional regulatory proteins that bind K43 acetylated AML1-ETO will have therapeutic efficacy against AML1-ETO driven AML. By defining the mechanisms required for the self-renewal of leukemia stem cells and for the expression of key genes that promote leukemia cell growth, we will devise new """"""""targeted"""""""" therapeutic strategies for this dreadful disease.
PI: Stephen D. Nimer, MD Relevance The successful targeting of leukemia stem (or initiating) cell self-renewal can hopefully improve clinical outcomes for patients with AML. We have made a key insight into the pathogenesis of AML1-ETO driven leukemia, and will hopefully develop novel ways of blocking this process.
|Shirakawa, Kotaro; Wang, Lan; Man, Na et al. (2016) Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity. Elife 5:|
|Liu, Fan; Wang, Lan; Perna, Fabiana et al. (2016) Beyond transcription factors: how oncogenic signalling reshapes the epigenetic landscape. Nat Rev Cancer 16:359-72|
|Hatlen, Megan A; Arora, Kanika; Vacic, Vladimir et al. (2016) Integrative genetic analysis of mouse and human AML identifies cooperating disease alleles. J Exp Med 213:25-34|
|Man, Na; Sun, Xiao-Jian; Tan, Yurong et al. (2016) Differential role of Id1 in MLL-AF9-driven leukemia based on cell of origin. Blood 127:2322-6|
|Perna, Fabiana; Vu, Ly P; Themeli, Maria et al. (2015) The polycomb group protein L3MBTL1 represses a SMAD5-mediated hematopoietic transcriptional program in human pluripotent stem cells. Stem Cell Reports 4:658-69|
|Mizutani, Shinsuke; Yoshida, Tatsushi; Zhao, Xinyang et al. (2015) Loss of RUNX1/AML1 arginine-methylation impairs peripheral T cell homeostasis. Br J Haematol 170:859-73|
|Wang, Lan; Man, Na; Sun, Xiao-Jian et al. (2015) Regulation of AKT signaling by Id1 controls t(8;21) leukemia initiation and progression. Blood 126:640-50|
|Zhao, Zhigang; Chen, Li; Dawlaty, Meelad M et al. (2015) Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice. Cell Rep 13:1692-704|
|Zong, Hongliang; Gozman, Alexander; Caldas-Lopes, Eloisi et al. (2015) A Hyperactive Signalosome in Acute Myeloid Leukemia Drives Addiction to a Tumor-Specific Hsp90 Species. Cell Rep 13:2159-73|
|Sun, Xiao-Jian; Man, Na; Tan, Yurong et al. (2015) The Role of Histone Acetyltransferases in Normal and Malignant Hematopoiesis. Front Oncol 5:108|
Showing the most recent 10 out of 20 publications