title: Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival.
abstract: FLT3/FLK2, a member of the receptor tyrosine kinase family, plays a critical role in maintenance of hematopoietic homeostasis, and the constitutively active form of the FLT3 mutation is one of the most common genetic abnormalities in acute myelogenous leukemia. In murine hematopoiesis, Flt3 is not expressed in self-renewing hematopoietic stem cells, but its expression is restricted to the multipotent and the lymphoid progenitor stages at which cells are incapable of self-renewal. We extensively analyzed the expression of Flt3 in human (h) hematopoiesis. Strikingly, in both the bone marrow and the cord blood, the human hematopoietic stem cell population capable of long-term reconstitution in xenogeneic hosts uniformly expressed Flt3. Furthermore, human Flt3 is expressed not only in early lymphoid progenitors, but also in progenitors continuously along the granulocyte/macrophage pathway, including the common myeloid progenitor and the granulocyte/macrophage progenitor. We further found that human Flt3 signaling prevents stem and progenitors from spontaneous apoptotic cell death at least through up-regulating Mcl-1, an indispensable survival factor for hematopoiesis. Thus, the distribution of Flt3 expression is considerably different in human and mouse hematopoiesis, and human FLT3 signaling might play an important role in cell survival, especially at stem and progenitor cells that are critical cellular targets for acute myelogenous leukemia transformation.
authors.affiliation: Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Yoshikane
authors.initials: Y
authors.lastname: Kikushige
authors.forename: Goichi
authors.initials: G
authors.lastname: Yoshimoto
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Iino
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Niiro
authors.forename: Katsuto
authors.initials: K
authors.lastname: Takenaka
authors.forename: Koji
authors.initials: K
authors.lastname: Nagafuji
authors.forename: Mine
authors.initials: M
authors.lastname: Harada
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Ishikawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000201:enzymology; D002470:Cell Survival; D005312:Fetal Blood / Q000166:cytology; D042381:Granulocyte Precursor Cells / Q000166:cytology / Q000201:enzymology*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology*; D006801:Humans; D054503:Lymphoid Progenitor Cells / Q000166:cytology / Q000201:enzymology; D008264:Macrophages / Q000166:cytology; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000201:enzymology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015854:Up-Regulation; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
chemical_list: C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3