Lookup NU author(s): Professor Olaf Heidenreich
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The activation of B-cell-specific genes, such as CD19 and PAX5, is a hallmark of t(8; 21) acute myeloid leukemia (AML) which expresses the translocation product RUNX1/ETO. PAX5 is an important regulator of B-lymphoid development and blocks myeloid differentiation when ectopically expressed. To understand the molecular mechanism of PAX5 deregulation, we examined its chromatin structure and regulation in t(8; 21) AML cells, non-t(8; 21) myeloid precursor control cells, and pre-B cells. In non-t(8; 21) myeloid precursors, PAX5 is poised for transcription, but is repressed by polycomb complexes. In t(8; 21) AML, PAX5 is not directly activated by RUNX1/ETO, but expression requires constitutive mitogen-activated protein (MAP) kinase signaling. Using a model of t(8; 21) carrying an activating KIT mutation, we demonstrate that deregulated MAP kinase signaling in t(8; 21) AML abrogates the association of polycomb complexes to PAX5 and leads to aberrant gene activation. Our findings therefore suggest a novel role of activating tyrosine kinase mutations in lineage-inappropriate gene expression in AML.
Author(s): Ray D, Kwon SY, Tagoh H, Heidenreich O, Ptasinska A, Bonifer C
Publication type: Article
Publication status: Published
Print publication date: 24/04/2013
ISSN (print): 0006-4971
ISSN (electronic): 1528-0020
Publisher: American Society of Hematology
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