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

Hassawi, M.; Shestakova, E.A.; Fournier, M.; Lebert-Ghali, C.; Vaisson, G.; Frison, H.; Sinnett, D.; Vidal, R.; Thompson, A.; Bijl, J.J.

Авторы: Hassawi Mona, Shestakova Elena A., Fournier Marilaine, Lebert-Ghali Charles-Étienne, Vaisson Gratianne, Frison Héloïse, Sinnett Daniel, Vidal Ramon, Thompson Alexander, Bijl Janet J.
Журнал: Developmental Dynamics
Том: 243
Номер: 1
Год издания: 2013
Издательство: John Wiley & Sons Inc.
Местоположение издательства: United States
Первая страница: 145
Последняя страница: 158
DOI: 10.1002/dvdy.24056
Аннотация: Background: The fusion protein E2A-PBX1 induces pediatric B cell leukemia in human. Previously, wereported 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 identifiedHoxa genes as potential collaborators to E2A-PBX1. Here we studied whether Hoxa9 couldenhance E2A-PBX1 leukemogenesis. Results: We show that Hoxa9 confers a proliferative advantage toE2A-PBX1 B cells. Transplantation experiments with E2A-PBX1 transgenic B cells overexpressingHoxa9 isolated from bone marrow chimeras showed that Hoxa9 accelerates the generation of E2APBX1B cell leukemia, but Hoxa9 is unable to transform B cells alone. Quantitative-reverse transcriptasepolymerase chain reaction analysis demonstrated a strong repression of B cell specific genes inthese E2A-PBX1/Hoxa9 leukemias in addition to Flt3 activation, indicating inhibition of B cell differentiationin combination with enhanced proliferation. Overexpression of Hoxa9 in established E2APBX1mouse leukemic B cells resulted in a growth advantage in vitro, which was also characterizedby an enhanced expression of Flt3. Conclusions: we show for the first time that Hoxa9 collaborateswith 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.VC 2013 Wiley Periodicals, Inc.Key words: Hox genes; oncogenes; transgenic mouse model; transcription factorsKey findings: Critical B cell genes are down-regulated in leukemias induced by E2A-PBX1 and Hoxa9. Hoxa9 mediated block in B cell differentiation in E2A-PBX1 leukemias involves Flt3.
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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 expressionстатья Исследовательская статья

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