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Hoxa9 collaborates with E2A-PBX1 in mouse B cell leukemia in association with Flt3 activation and decrease of B cell gene expression

Hassawi, Mona; Shestakova, Elena A.; Fournier, Marilaine; Lebert-Ghali, Charles-�tienne; Vaisson, Gratianne; Frison, H�lo�se; Sinnett, Daniel; Vidal, Ramon; Thompson, Alexander; Bijl, Janet J.

Authors

Mona Hassawi

Elena A. Shestakova

Marilaine Fournier

Charles-�tienne Lebert-Ghali

Gratianne Vaisson

H�lo�se Frison

Daniel Sinnett

Ramon Vidal

Janet J. Bijl



Abstract

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. © 2013 Wiley Periodicals, Inc.

Journal Article Type Article
Acceptance Date Aug 27, 2013
Online Publication Date Oct 7, 2013
Publication Date 2014-01
Deposit Date May 12, 2017
Journal Developmental Dynamics
Print ISSN 1058-8388
Electronic ISSN 1097-0177
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 243
Issue 1
Pages 145-158
DOI https://doi.org/10.1002/dvdy.24056
Keywords Hox genes; oncogenes; transgenic mouse model; transcription factors
Public URL https://nottingham-repository.worktribe.com/output/997440
Publisher URL http://onlinelibrary.wiley.com/doi/10.1002/dvdy.24056/abstract