title: Lineage-inappropriate PAX5 expression in t(8;21) acute myeloid leukemia requires signaling-mediated abrogation of polycomb repression.
abstract: 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.
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Debleena
authors.initials: D
authors.lastname: Ray
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Kwon
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tagoh
authors.forename: Olaf
authors.initials: O
authors.lastname: Heidenreich
authors.forename: Anetta
authors.initials: A
authors.lastname: Ptasinska
authors.forename: Constanze
authors.initials: C
authors.lastname: Bonifer
mesh_terms: D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D015536:Down-Regulation / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008954:Models, Biological; D051757:PAX5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014178:Translocation, Genetic
chemical_list: D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D063146:Polycomb-Group Proteins