Flt3 is dispensable to the Hoxa9/Meis1 leukemogenic cooperation.
HOX genes, MEIS1, and FLT3 are frequently up-regulated in human myeloid leukemias. Meis1 cooperates with Hox genes to induce leukemias in mice, hypothetically the consequence of Meis1-induced Flt3 overexpression. To test this, we compared the properties of Flt3(-/-) and Flt3(+/+) progenitors transduced with Hoxa9 or Hoxa9/Meis1. In a myeloid clonogenic assay, Meis1 greatly enhanced the proliferation of Hoxa9-expressing cells, massively up-regulating Flt3 protein. However, the transforming potential of Hoxa9/Meis1 was unaltered in Flt3(-/-) cells. All mice that received Hoxa9/Meis1-transduced progenitors succumbed to rapid acute myeloid leukemias regardless of Flt3 genotype. Flt3 expression levels in leukemic blasts did not correlate with parameters reflecting their proliferative rate or their impaired differentiation. Furthermore, analysis of c-Myb expression levels in Hoxa9/Meis1-transformed cells showed that the up-regulation of this critical downstream effector was independent of Flt3. Altogether, our findings demonstrate that Flt3 is dispensable to the oncogenic cooperation of Meis1 with Hoxa9.
Morgado
Ester
E
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7151, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France.
Albouhair
Stéphanie
S
Lavau
Catherine
C
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D005838:Genotype; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D014411:Neoplastic Stem Cells; D020598:Proto-Oncogene Proteins c-myb / Q000096:biosynthesis / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000096:biosynthesis* / Q000235:genetics
D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D020598:Proto-Oncogene Proteins c-myb; C097899:homeobox protein HOXA9; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3