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The IRX1/HOXA connection : insights into a novel t(4;11)- specific cancer mechanism
- 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.
Author: | Alessa Carina Kühn, Denise Löscher, Rolf MarschalekORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-451121 |
DOI: | https://doi.org/10.18632/oncotarget.9241 |
ISSN: | 1949-2553 |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/27175594 |
Parent Title (English): | OncoTarget |
Publisher: | Impact Journals LLC |
Place of publication: | [s. l.] |
Document Type: | Article |
Language: | English |
Year of Completion: | 2016 |
Date of first Publication: | 2016/05/09 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2017/11/30 |
Tag: | EGR1/2/3; HOXA profile; HOXB4; IRX1; MLL-r leukemia |
Volume: | 7 |
Issue: | 23 |
Page Number: | 12 |
First Page: | 35341 |
Last Page: | 35352 |
Note: | All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License. |
HeBIS-PPN: | 425147339 |
Institutes: | Biochemie, Chemie und Pharmazie / Pharmazie |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Open-Access-Publikationsfonds: | Biochemie, Chemie und Pharmazie |
Licence (German): | Creative Commons - Namensnennung 3.0 |