Human Flt3 Is Expressed at the Hematopoietic Stem Cell and the Granulocyte/Macrophage Progenitor Stages to Maintain Cell Survival

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 e...

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Published inThe Journal of immunology (1950) Vol. 180; no. 11; pp. 7358 - 7367
Main Authors Kikushige, Yoshikane, Yoshimoto, Goichi, Miyamoto, Toshihiro, Iino, Tadafumi, Mori, Yasuo, Iwasaki, Hiromi, Niiro, Hiroaki, Takenaka, Katsuto, Nagafuji, Koji, Harada, Mine, Ishikawa, Fumihiko, Akashi, Koichi
Format Journal Article
LanguageEnglish
Published United States Am Assoc Immnol 01.06.2008
Subjects
Animals
Apoptosis
Bone Marrow Cells - enzymology
Cell Survival
Fetal Blood - cytology
fms-Like Tyrosine Kinase 3 - metabolism
Granulocyte Precursor Cells - cytology
Granulocyte Precursor Cells - enzymology
Hematopoiesis
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - enzymology
Humans
Lymphoid Progenitor Cells - cytology
Lymphoid Progenitor Cells - enzymology
Macrophages - cytology
Mice
Myeloid Cell Leukemia Sequence 1 Protein
Myeloid Progenitor Cells - cytology
Myeloid Progenitor Cells - enzymology
Proto-Oncogene Proteins c-bcl-2 - metabolism
Up-Regulation
Online AccessGet full text

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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.
AbstractList 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.
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.
Author Iwasaki, Hiromi
Ishikawa, Fumihiko
Kikushige, Yoshikane
Miyamoto, Toshihiro
Harada, Mine
Yoshimoto, Goichi
Iino, Tadafumi
Nagafuji, Koji
Akashi, Koichi
Niiro, Hiroaki
Takenaka, Katsuto
Mori, Yasuo
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  fullname: Iwasaki, Hiromi
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  fullname: Niiro, Hiroaki
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  fullname: Takenaka, Katsuto
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  fullname: Nagafuji, Koji
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  fullname: Harada, Mine
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  fullname: Ishikawa, Fumihiko
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  fullname: Akashi, Koichi
BackLink https://www.ncbi.nlm.nih.gov/pubmed/18490735$$D View this record in MEDLINE/PubMed
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Snippet FLT3/FLK2, a member of the receptor tyrosine kinase family, plays a critical role in maintenance of hematopoietic homeostasis, and the constitutively active...
Abstract FLT3/FLK2, a member of the receptor tyrosine kinase family, plays a critical role in maintenance of hematopoietic homeostasis, and the constitutively...
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SubjectTerms Animals
Apoptosis
Bone Marrow Cells - enzymology
Cell Survival
Fetal Blood - cytology
fms-Like Tyrosine Kinase 3 - metabolism
Granulocyte Precursor Cells - cytology
Granulocyte Precursor Cells - enzymology
Hematopoiesis
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - enzymology
Humans
Lymphoid Progenitor Cells - cytology
Lymphoid Progenitor Cells - enzymology
Macrophages - cytology
Mice
Myeloid Cell Leukemia Sequence 1 Protein
Myeloid Progenitor Cells - cytology
Myeloid Progenitor Cells - enzymology
Proto-Oncogene Proteins c-bcl-2 - metabolism
Up-Regulation
Title Human Flt3 Is Expressed at the Hematopoietic Stem Cell and the Granulocyte/Macrophage Progenitor Stages to Maintain Cell Survival
URI http://www.jimmunol.org/cgi/content/abstract/180/11/7358
https://www.ncbi.nlm.nih.gov/pubmed/18490735
https://search.proquest.com/docview/20725027
https://search.proquest.com/docview/70767144
Volume 180
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