title: The IRX1/HOXA connection: insights into a novel t(4;11)- specific cancer mechanism.
abstract: One hallmark of MLL-r leukemia is the highly specific gene expression signature indicative for commonly deregulated target genes. An usual read-out for this transcriptional deregulation is the HOXA gene cluster, where upregulated HOXA genes are detected in MLL-r AML and ALL patients. In case of t(4;11) leukemia, this simple picture becomes challenged, because these patients separate into HOXAhi- and HOXAlo-patients. HOXAlo-patients showed a reduced HOXA gene transcription, but instead overexpressed the homeobox gene IRX1. This transcriptional pattern was associated with a higher relapse rate and worse outcome. Here, we demonstrate that IRX1 binds to the MLL-AF4 complex at target gene promotors and counteract its promotor activating function. In addition, IRX1 induces transcription of HOXB4 and EGR family members. HOXB4 is usually a downstream target of c-KIT, WNT and TPO signaling pathways and necessary for maintaining and expanding in hematopoietic stem cells. EGR proteins control a p21-dependent quiescence program for hematopoietic stem cells. Both IRX1-dependend actions may help t(4;11) leukemia cells to establish a stem cell compartment. We also demonstrate that HDACi administration is functionally interfering with IRX1 and MLL-AF4, a finding which could help to improve new treatment options for t(4;11) patients.
authors.affiliation: Institute of Pharmaceutical Biology/DCAL, Goethe-University of Frankfurt, Biocenter, D-60438 Frankfurt/Main, Germany.
authors.forename: Alessa
authors.initials: A
authors.lastname: Kühn
authors.affiliation: Institute of Pharmaceutical Biology/DCAL, Goethe-University of Frankfurt, Biocenter, D-60438 Frankfurt/Main, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Löscher
authors.affiliation: Institute of Pharmaceutical Biology/DCAL, Goethe-University of Frankfurt, Biocenter, D-60438 Frankfurt/Main, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Marschalek
mesh_terms: D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C501591:IRX1 protein, human; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C088144:HoxA protein
keywords: EGR1/2/3; HOXA profile; HOXB4; IRX1; MLL-r leukemia