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Upregulation of Flt3 is a passive event in Hoxa9/Meis1-induced acute myeloid leukemia in mice.

Journal article
Authors Anna Staffas
Laleh S. Arabanian
S. Y. Wei
Ann Jansson
Sara Ståhlman
Pegah Johansson
Linda Fogelstrand
J Cammenga
F Kuchenbauer
Lars Palmqvist
Published in Oncogene
Volume 36
Pages 1516–1524
ISSN 1476-5594
Publication year 2017
Published at Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Pages 1516–1524
Language en
Links dx.doi.org/10.1038/onc.2016.318
Keywords AML, FLT3, HOXA9, MEIS1
Subject categories Hematology, Molecular biology, Molecular medicine (genetics and pathology)

Abstract

HOXA9, MEIS1 and FLT3 are genes frequently upregulated in human acute myeloid leukemia. Hoxa9 and Meis1 also cooperate to induce aggressive AML with high Flt3 expression in mice, suggesting an important role for Flt3 in Hoxa9/Meis1-induced leukemogenesis. To define the role of Flt3 in AML with high Hoxa9/Meis1, we treated mice with Hoxa9/Meis1-induced AML with the Flt3 inhibitor AC220, used an Flt3-ligand (FL-/-) knockout model, and investigated whether overexpression of Flt3 could induce leukemia together with overexpression of Hoxa9. Flt3 inhibition by AC220 did not delay AML development in mice transplanted with bone marrow cells overexpressing Hoxa9 and Meis1. In addition, Hoxa9/Meis1 cells induced AML in FL-/- mice as rapid as in wild-type mice. However, FL-/- mice had reduced organ infiltration compared with wild-type mice, suggesting some Flt3-dependent effect on leukemic invasiveness. Interestingly, leukemic Hoxa9/Meis1 cells from sick mice expressed high levels of Flt3 regardless of presence of its ligand, showing that Flt3 is a passive marker on these cells. In line with this, combined engineered overexpression of Flt3 and Hoxa9 did not accelerate the progression to AML. We conclude that the Hoxa9- and Meis1-associated upregulation of Flt3 is not a requirement for leukemic progression induced by Hoxa9 and Meis1.Oncogene advance online publication, 12 September 2016; doi:10.1038/onc.2016.318.

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