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* Medicine and Biosystemic Science, and
Center for Cellular and Molecular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, and
Research Unit for Human Disease Model, RIKEN Center for Allergy and Immunology, Kanagawa, Japan; and
Department of Cancer Immunology and AIDS Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology in Japan (19659248 to T.M., and 17109010 and 17047029 to K.A.) and the Mochida Memorial Foundation for Medical and Pharmaceutical Research (to T.M.).
2 Address correspondence and reprint requests to Dr. Koichi Akashi, Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan. E-mail address: akashi{at}med.kyushu-u.ac.jp
3 Abbreviations used in this paper: HSC, hematopoietic stem cell; AML, acute myelogenous leukemia; BM, bone marrow; KLS, c-Kit+Lin–Sca-1+; LT-HSC, HSC with long-term reconstituting activity; ST-HSC, short-term HCS; m, murine; h, human; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; GM, granulocyte/macrophage; GMP, GM progenitor; MEP, megakaryocyte/erythrocyte progenitor; CB, cord blood; MegE, megakaryocyte/erythrocyte; FL, Flt3 ligand; PI, propidium iodide; SCF, stem cell factor; Tpo, thrombopoietin; Epo, erythropoietin; CFU-GEMM, CFU-granulocyte/erythroid/macrophage/megakaryocyte; RTK, receptor tyrosine kinase; ITD, internal tandem duplication.
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