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.
|Hoshii, Takayuki; Cifani, Paolo; Feng, Zhaohui et al. (2018) A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response. Cell 172:1007-1021.e17|
|Cusan, Monica; Cai, Sheng F; Mohammad, Helai P et al. (2018) LSD1 inhibition exerts its antileukemic effect by recommissioning PU.1- and C/EBP?-dependent enhancers in AML. Blood 131:1730-1742|
|Toska, Eneda; Osmanbeyoglu, Hatice U; Castel, Pau et al. (2017) PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D. Science 355:1324-1330|
|Valerio, Daria G; Xu, Haiming; Chen, Chun-Wei et al. (2017) Histone Acetyltransferase Activity of MOF Is Required for MLL-AF9 Leukemogenesis. Cancer Res 77:1753-1762|
|Valerio, Daria G; Xu, Haiming; Eisold, Meghan E et al. (2017) Histone acetyltransferase activity of MOF is required for adult but not early fetal hematopoiesis in mice. Blood 129:48-59|
|Wan, Liling; Wen, Hong; Li, Yuanyuan et al. (2017) ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia. Nature 543:265-269|
|Kühn, Michael W M; Song, Evelyn; Feng, Zhaohui et al. (2016) Targeting Chromatin Regulators Inhibits Leukemogenic Gene Expression in NPM1 Mutant Leukemia. Cancer Discov 6:1166-1181|
|Xu, Haiming; Valerio, Daria G; Eisold, Meghan E et al. (2016) NUP98 Fusion Proteins Interact with the NSL and MLL1 Complexes to Drive Leukemogenesis. Cancer Cell 30:863-878|
|Brien, Gerard L; Valerio, Daria G; Armstrong, Scott A (2016) Exploiting the Epigenome to Control Cancer-Promoting Gene-Expression Programs. Cancer Cell 29:464-476|
|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|
Showing the most recent 10 out of 29 publications