title: Fyn is not essential for Bcr-Abl-induced leukemogenesis in mouse bone marrow transplantation models.
abstract: The Bcr-Abl oncogene causes human Philadelphia chromosome-positive (Ph(+)) leukemias, including B-cell acute lymphoblastic leukemia (B-ALL) and chronic myeloid leukemia (CML) with chronic phase (CML-CP) to blast crisis (CML-BC). Previous studies have demonstrated that Src family kinases are required for the induction of B-ALL, but not for CML, which is induced by Bcr-Abl in mice. In contrast, it has been reported that Fyn is up-regulated in human CML-BC compared with CML-CP, implicating Fyn in the blast crisis transition. Here, we aimed to delineate the exact role of Fyn in the induction/progression of Ph(+) leukemias. We found that Fyn is expressed in mouse hematopoietic cells at varying stages of development, including c-kit(+)Sca-1(+)Lin(-) cells. Notably, Fyn is highly expressed in some of human lymphomas, but not in human Ph(+) leukemias including CML-BC. In mouse bone marrow transplantation models, mice transplanted with wild-type or Fyn-deficient bone marrow cells transduced with Bcr-Abl showed no differences in the development of B-ALL or CML-like diseases. Similarly, Fyn deficiency failed to impact the development of myeloid CML-BC induced by Bcr-Abl and Hes1. Elevated expression of Fyn was not found in mouse samples of Bcr-Abl-mediated CML- and CML-BC-like diseases. Thus, Fyn is not required for the pathogenesis of Bcr-Abl-mediated leukemias.
authors.affiliation: Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Doki
authors.forename: Jiro
authors.initials: J
authors.lastname: Kitaura
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Uchida
authors.forename: Daichi
authors.initials: D
authors.lastname: Inoue
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kagiyama
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Togami
authors.forename: Masamichi
authors.initials: M
authors.lastname: Isobe
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ito
authors.forename: Akie
authors.initials: A
authors.lastname: Maehara
authors.forename: Kumi
authors.initials: K
authors.lastname: Izawa
authors.forename: Naoko
authors.initials: N
authors.lastname: Kato
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Oki
authors.forename: Yuka
authors.initials: Y
authors.lastname: Harada
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakahara
authors.forename: Hironori
authors.initials: H
authors.lastname: Harada
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000503:physiopathology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000503:physiopathology; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000503:physiopathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000503:physiopathology; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics* / Q000502:physiology; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D016044:Fusion Proteins, bcr-abl; D018398:Homeodomain Proteins; D051076:Proto-Oncogene Proteins c-fyn; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C494957:FYN protein, human; C494960:Fyn protein, mouse