title: Tyk2 is dispensable for induction of myeloproliferative disease by mutant FLT3.
abstract: Internal tandem duplication of FLT3 tyrosine kinase (FLT3-ITD) is the most prevalent mutation found in acute myelogenous leukemia (AML), having been identified in 20% to 30% of all AML patients. We have previously shown that FLT3-ITD signals mainly through the signal transducer and activator of transcription 5 (STAT5) pathway and have suggested the possible involvement of Tyk2 in STAT5 activation by FLT3-ITD. The present study addressed the role of Tyk2 in FLT3-ITD signaling in a murine bone marrow transplantation (BMT) model. Transplantation of wild-type bone marrow cells transduced with the FLT3-ITD gene induced lethal myeloproliferative disease (MPD) in the recipient mice at a median latency of 89 days. Interestingly, some mice presented the proliferation of B- or T-lymphoid blasts in various organs, a presentation that resembled acute lymphoblastic leukemia (ALL). Mice that received Tyk2-deficient bone marrow cells transduced with FLT3-ITD developed lethal MPD with a disease latency (median, 100 days) and pathologic picture similar to those of mice that received wild-type bone marrow cells. These results indicate that (1) Tyk2 is not essential for MPD induction by FLT3-ITD and (2) FLT3-ITD by itself can induce ALL in a murine BMT model.
authors.affiliation: Center of Excellence, Institute of Medical Science, University of Tokyo, Tokyo, Japan. hnakajim@ims.u-tokyo.ac.jp.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakajima
authors.forename: Fumi
authors.initials: F
authors.lastname: Shibata
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kumagai
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimoda
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016254:Mutagenesis, Insertional; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D053634:TYK2 Kinase; D013997:Time Factors; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D050799:STAT5 Transcription Factor; C497971:Flt3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse