Hassawi and Dr. Shestakova contributed equally to the manuscript.
Special Issue Research Article
Hoxa9 collaborates with E2A-PBX1 in mouse B cell leukemia in association with Flt3 activation and decrease of B cell gene expression
Version of Record online: 7 OCT 2013
Copyright © 2013 Wiley Periodicals, Inc.
Special Issue: Hox/Tale Transcription Factors in Development and Disease
Volume 243, Issue 1, pages 145–158, January 2014
How to Cite
Hassawi, M., Shestakova, E. A., Fournier, M., Lebert-Ghali, C.-É., Vaisson, G., Frison, H., Sinnett, D., Vidal, R., Thompson, A. and Bijl, J. J. (2014), Hoxa9 collaborates with E2A-PBX1 in mouse B cell leukemia in association with Flt3 activation and decrease of B cell gene expression. Dev. Dyn., 243: 145–158. doi: 10.1002/dvdy.24056
- Issue online: 20 DEC 2013
- Version of Record online: 7 OCT 2013
- Accepted manuscript online: 2 SEP 2013 01:59AM EST
- Manuscript Accepted: 27 AUG 2013
- Manuscript Revised: 26 AUG 2013
- Manuscript Received: 1 MAY 2013
- Leukemia and Lymphoma Society of Canada
- Canadian Cancer Society Research Institute. Grant Number: 20399
- Hox genes;
- transgenic mouse model;
- transcription factors
Background: The fusion protein E2A-PBX1 induces pediatric B cell leukemia in human. Previously, we reported oncogenic interactions between homeobox (Hox) genes and E2A-PBX1 in murine T cell leukemia. A proviral insertional mutagenesis screen with our E2A-PBX1 B cell leukemia mouse model identified Hoxa genes as potential collaborators to E2A-PBX1. Here we studied whether Hoxa9 could enhance E2A-PBX1 leukemogenesis. Results: We show that Hoxa9 confers a proliferative advantage to E2A-PBX1 B cells. Transplantation experiments with E2A-PBX1 transgenic B cells overexpressing Hoxa9 isolated from bone marrow chimeras showed that Hoxa9 accelerates the generation of E2A-PBX1 B cell leukemia, but Hoxa9 is unable to transform B cells alone. Quantitative-reverse transcriptase polymerase chain reaction analysis demonstrated a strong repression of B cell specific genes in these E2A-PBX1/Hoxa9 leukemias in addition to Flt3 activation, indicating inhibition of B cell differentiation in combination with enhanced proliferation. Overexpression of Hoxa9 in established E2A-PBX1 mouse leukemic B cells resulted in a growth advantage in vitro, which was also characterized by an enhanced expression of Flt3. Conclusions: we show for the first time that Hoxa9 collaborates with E2A-PBX1 in the oncogenic transformation of B cells in a mouse model that involves Flt3 signaling, which is potentially relevant to human disease. Developmental Dynamics 243:145–158, 2014. © 2013 Wiley Periodicals, Inc.