0000000000050090
AUTHOR
Nan Zhu
STAT5 is crucial to maintain leukemic stem cells in acute myelogenous leukemias induced by MOZ-TIF2.
Abstract MOZ-TIF2 is a leukemogenic fusion oncoprotein that confers self-renewal capability to hematopoietic progenitor cells and induces acute myelogenous leukemia (AML) with long latency in bone marrow transplantation assays. Here, we report that FLT3-ITD transforms hematopoietic cells in cooperation with MOZ-TIF2 in vitro and in vivo. Coexpression of FLT3-ITD confers growth factor independent survival/proliferation, shortens disease latency, and results in an increase in the number of leukemic stem cells (LSC). We show that STAT5, a major effector of aberrant FLT3-ITD signal transduction, is both necessary and sufficient for this cooperative effect. In addition, STAT5 signaling is essent…
MLL-Rearranged Leukemia Is Dependent on Aberrant H3K79 Methylation by DOT1L
SummaryThe histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-a…
Demonstration of a Role for Dot1l In MLL-Rearranged Leukemia Using a Conditional Loss of Function Model
Abstract Abstract 62 Leukemias associated with translocations of the Mixed Lineage Leukemia (MLL) gene account for a significant percentage of both AML and ALL, and often carry a poor prognosis. The exact molecular mechanisms by which MLL-fusion proteins transform cells are incompletely understood. One proposed model involves the aberrant activation of transcriptional programs through epigenetic changes that ultimately lead to leukemogenesis. The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been shown to be recruited by the most common MLL fusion proteins, and MLL fusion protein target loci are associated with H3K79 methylation (H3K79me2/3) in mouse models and MLL-rearranged huma…