The IRX1/HOXA connection: insights into a novel t(4;11)- specific cancer mechanism
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Alessa Kühn1, Denise Löscher1, Rolf Marschalek1
1Institute of Pharmaceutical Biology/DCAL, Goethe-University of Frankfurt, Biocenter, D-60438 Frankfurt/Main, Germany
Rolf Marschalek, email: Rolf.Marschalek@em.uni-frankfurt.de
Keywords: MLL-r leukemia, HOXA profile, IRX1, HOXB4, EGR1/2/3
Received: February 12, 2016 Accepted: April 16, 2016 Published: May 9, 2016
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.
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