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Upregulation of Flt3 is a passive event in Hoxa9/Meis1-induced acute myeloid leukemia in mice
University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
University of Gothenburg, Sweden.
University of Gothenburg, Sweden; Sahlgrens University Hospital, Sweden.
Sahlgrens University Hospital, Sweden.
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2017 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 36, no 11, 1516-1524 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 36, no 11, 1516-1524 p.
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-136643DOI: 10.1038/onc.2016.318ISI: 000397458100006PubMedID: 27617578OAI: oai:DiVA.org:liu-136643DiVA: diva2:1089840
Note

Funding Agencies|Swedish Cancer Society [CAN2014/525]; Vastra Gotalandsregionen [ALFGBG-431881]; Deutsche Krebshilfe [109420]; European Hematology Association; Deutsche Forschungsgemeinschaft [SFB 1074]; Assar Gabrielssons foundation

Available from: 2017-04-21 Created: 2017-04-21 Last updated: 2017-05-23

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Cammenga, Jörg
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Division of Surgery, Orthopedics and OncologyFaculty of Medicine and Health SciencesDepartment of Haematology
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