Lineage inappropriate PAX5 expression in t(8;21) acute myeloid leukemia requires signalling mediated abrogation of polycomb repression
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
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 in 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 MAP kinase signalling. Using a model of t(8;21) carrying an activating KIT mutation we demonstrate that deregulated MAP kinase signalling in t(8;21) AML abrogates the association of polycomb 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.
|Publication status||Published - 24 Apr 2013|