Acute leukemias that bear chromosomal translocations at 11q23 possess rearrangements of the Mixed Lineage Leukemia gene (MLL, HRX, ALL-1). More than 40 different MLL translocations have been reported, but the t(4;11) (MLL-AF4) is particularly common in leukemias diagnosed as ALL or mixed-lineage leukemia. Patients with MLL-AF4 leukemias have a poor prognosis. This is particularly true for infant leukemia where approximately 80% of cases will harbor rearrangement of the MLL gene. We have recently developed a conditional mouse model of Mll-AF4 ALL that recapitulates the gene expression profiles and histone methylation profiles of human MLL-AF4 ALL. Experiments described in this proposal will build upon these previous studies and characterize leukemia development with a particular focus on histone methylation. We will determine which cell types are permissive for Mll-AF4 leukemia development including hematopoietic stem cells (HSC) and early lymphoid committed cells. We will also determine if MLL-AF4 leukemia cell survival is dependent upon the histone methyltransferase Dot1L. These studies will provide a highly detailed characterization of the cells of origin of Mll-AF4 ALL, and begin to determine if histone methyltransferases are potential therapeutic targets in this disease.
The MLL-AF4 translocation is found in acute lymphoblastic leukemias that confer a poor prognosis. We will use sophisticated mouse models and human leukemia cells, to characterize the abberant molecuar and cellular processes that are induded during leukemia development, and determine if inhibition of specific histone methyltransferases could be a therapeutic target in this disease.
|Brien, Gerard L; Valerio, Daria G; Armstrong, Scott A (2016) Exploiting the Epigenome to Control Cancer-Promoting Gene-Expression Programs. Cancer Cell 29:464-76|
|Zhu, Nan; Chen, Mo; Eng, Rowena et al. (2016) MLL-AF9- and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C. J Clin Invest 126:997-1011|
|KÃ¼hn, Michael W M; Hadler, Michael J; Daigle, Scott R et al. (2015) MLL partial tandem duplication leukemia cells are sensitive to small molecule DOT1L inhibition. Haematologica 100:e190-3|
|Chen, Chun-Wei; Koche, Richard P; Sinha, Amit U et al. (2015) DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia. Nat Med 21:335-43|
|Chen, Chun-Wei; Armstrong, Scott A (2015) Targeting DOT1L and HOX gene expression in MLL-rearranged leukemia and beyond. Exp Hematol 43:673-84|
|Koche, Richard P; Armstrong, Scott A (2014) Genomic dark matter sheds light on EVI1-driven leukemia. Cancer Cell 25:407-8|
|Deshpande, Aniruddha J; Deshpande, Anagha; Sinha, Amit U et al. (2014) AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes. Cancer Cell 26:896-908|
|Hanoun, Maher; Zhang, Dachuan; Mizoguchi, Toshihide et al. (2014) Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell 15:365-75|
|Bruedigam, Claudia; Bagger, Frederik O; Heidel, Florian H et al. (2014) Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy. Cell Stem Cell 15:775-90|
|Santos, Margarida A; Faryabi, Robert B; Ergen, Aysegul V et al. (2014) DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier. Nature 514:107-11|
Showing the most recent 10 out of 20 publications