Upregulation of Flt3 is a passive event in Hoxa9/Meis1-induced acute myeloid leukemia in mice.
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.
Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.|Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
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Staffas
Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
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Arabanian
Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.|Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
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Wei
Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
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Jansson
Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.|Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
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Ståhlman
Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.|Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
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Johansson
Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.|Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
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Fogelstrand
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.|Department of Hematology, Linköping University Hospital, Linköping, Sweden.
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Cammenga
Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.
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Kuchenbauer
Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.|Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
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Palmqvist
D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D015415:Biomarkers; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D051379:Mice; D018345:Mice, Knockout; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D010671:Phenylurea Compounds / Q000494:pharmacology; D011379:Prognosis; D015398:Signal Transduction / Q000187:drug effects; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D052160:Benzothiazoles; D015415:Biomarkers; D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; C097899:homeobox protein HOXA9; C544967:quizartinib; D051941:fms-Like Tyrosine Kinase 3