FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model.
Activating mutations of the Fms-like tyrosine kinase 3 (FLT3) receptor are the most common genetic alteration in acute myeloid leukemia (AML). Two distinct groups of FLT3 mutations are found: internal tandem duplications (ITDs) of the juxtamembrane region and point mutations within the tyrosine kinase domain (TKD). Recently, point mutations within the activation loop of FLT3 have also been described in childhood acute lymphoblastic leukemia (ALL). FLT3-ITD has been shown to induce a myeloproliferative syndrome in a murine bone marrow transplantation model. The phenotype of FLT3-TKD in mice has not yet been investigated. We transduced murine bone marrow with retrovirus-expressing FLT3-TKD mutants or FLT3-ITD and transplanted these cells into lethally irradiated mice. Mice that received a transplant of FLT3-ITD developed an oligoclonal myeloproliferative disease as previously described. In contrast, FLT3-TKD mutants induced an oligoclonal lymphoid disorder with longer latency and distinct hematologic manifestations: importantly, induction of the lymphoid phenotype was not due to a low number of transplanted cells. The lymphoid manifestation and longer latency of FLT3-TKD compared with FLT3-ITD mutants together with the lack of influence of FLT3-TKD mutations on the clinical outcome of patients with AML suggest differences in cell signaling between FLT3-TKD mutants and FLT3-ITDs. Indeed strong signal transducers and activators of transcription 5 (STAT5) activation could only be demonstrated for FLT3-ITDs.
Grundler
Rebekka
R
Department of Internal Medicine III, Technical University of Munich, Ismaningerstr 22, 81675 Munich, Germany.
Miething
Cornelius
C
Thiede
Christian
C
Peschel
Christian
C
Duyster
Justus
J
D000818:Animals; D015139:Blotting, Southern; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D002469:Cell Separation; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D015151:Immunoblotting; D016130:Immunophenotyping; D047468:Immunoprecipitation; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008894:Milk Proteins / Q000378:metabolism; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics; D010641:Phenotype; D017354:Point Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry*; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics*; D011994:Recombinant Proteins / Q000737:chemistry; D012190:Retroviridae / Q000235:genetics; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013163:Splenomegaly / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D049452:Green Fluorescent Proteins; C497971:Flt3 protein, mouse; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3