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Hematopoiesis
The homeobox transcription factor HB9 induces senescence and blocks differentiation in hematopoietic stem and progenitor cells
Ferrata Storti Foundation
Deborah Ingenhag,1 Sven Reister,1 Franziska Auer,1 Sanil Bhatia,1 Sarah Wildenhain,1 Daniel Picard,1,2 Marc Remke,1,2 Jessica I. Hoell,1 Andreas Kloetgen,1,3 Dennis Sohn,4 Reiner U. Jänicke,4 Gesine Koegler,5 Arndt Borkhardt1 and Julia Hauer1
1Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty of Heinrich-Heine-University, Düsseldorf; 2Department of Pediatric Neuro- Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg; 3Computational Biology of Infection Research, Helmholtz Center for Infection Research, Braunschweig; 4Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, Medical Faculty of Heinrich-Heine-University, Düsseldorf and 5Institute for Transplantation Diagnostics and Cell Therapeutics, Medical Faculty of Heinrich-Heine-University, Düsseldorf, Germany
Haematologica 2019 Volume 104(1):35-46
ABSTRACT
The homeobox gene HLXB9 encodes for the transcription factor HB9, which is essential for pancreatic as well as motor neuronal development. Beside its physiological expression pattern, aberrant HB9 expression has been observed in several neoplasias. Especially in infant translocation t(7;12) acute myeloid leukemia, aberrant HB9 expression is the only known molecular hallmark and is assumed to be a key factor in leukemic transformation. However, so far, only poor functional data exist addressing the oncogenic potential of HB9 or its influence on hematopoiesis. We investigated the influence of HB9 on cell proliferation and cell cycle in vitro, as well as on hematopoietic stem cell differentiation in vivo using murine and human model systems. In vitro, HB9 expression led to premature senescence in human HT1080 and murine NIH3T3 cells, providing for the first time evidence for an onco- genic potential of HB9. Onset of senescence was characterized by induc- tion of the p53-p21 tumor suppressor network, resulting in growth arrest, accompanied by morphological transformation and expression of senescence-associated β-galactosidase. In vivo, HB9-transduced primary murine hematopoietic stem and progenitor cells underwent a profound differentiation arrest and accumulated at the megakaryocyte/erythro- cyte progenitor stage. In line, gene expression analyses revealed de novo expression of erythropoiesis-related genes in human CD34+ hematopoi- etic stem and progenitor cells upon HB9 expression. In summary, the novel findings of HB9-dependent premature senescence and myeloid- biased perturbed hematopoietic differentiation, for the first time shed light on the oncogenic properties of HB9 in translocation t(7;12) acute myeloid leukemia.
Introduction
Senescence serves as a tumor-suppressive mechanism and prevents prolifera- tion of cells which have acquired an irreversible DNA-damage.1 Physiologically this results from continued telomere shortening during each round of replication and is therefore called replicative senescence. Onset of senescence is character- ized by induction of tumor-suppressor networks such as p53-p21, followed by cell cycle arrest, morphological transformation, and increased β-galactosidase activity.1 Induction of senescence prior to the replication limit is termed prema- ture senescence. In this case, DNA-damage is caused by genotoxic or replicative stress, for example due to mutagenic agents or oncogene expression.2 This was shown for strong oncogenes like RAS and MYC, which induce senescence in fibroblasts in the absence of other transforming mutations, so called oncogene- induced senescence.3,4
Correspondence:
Julia.Hauer@med.uni-duesseldorf.de
Received: January 25, 2018. Accepted: July 30, 2018. Pre-published: August 9, 2018.
doi:10.3324/haematol.2018.189407
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/1/35
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