title: Homeostasis of hematopoietic stem cells regulated by the myeloproliferative disease associated-gene product Lnk/Sh2b3 via Bcl-xL.
abstract: Hematopoietic stem cells (HSCs) are maintained at a very low frequency in adult bone marrow under steady-state conditions. However, it is not fully understood how homeostasis of bone marrow HSCs is maintained. We attempted to identify a key molecule involved in the regulation of HSC numbers, a factor that, in the absence of Lnk, leads to HSC expansion. Here, we demonstrate that upon stimulation with thrombopoietin, expression of Bcl-xL, an antiapoptotic protein, was highly enhanced in Lnk-deficient HSCs compared to normal HSCs. As a result, Lnk-deficient HSCs underwent reduced apoptosis following exposure to lethal radiation. Downregulation of Bcl-xL expression in Lnk-deficient HSCs by short-hairpin RNA resulted in a great reduction of their capacity for reconstitution. These findings suggest that Lnk/Sh2b3 constrains the expression of Bcl-xL and that the loss of Lnk/Sh2b3 function enhances survival of HSCs by inhibiting apoptosis. Furthermore, our observations indicate that HSCs in patients with an Lnk/Sh2b3 mutation might become resistant to apoptosis due to thrombopoietin-mediated enhanced expression of Bcl-xL. Consequently, reduced apoptosis could facilitate accumulation of HSCs with oncogenic mutations leading to development of myeloproliferative disorders.
authors.affiliation: Laboratory of Stem Cell Therapy, Center for Experimental Medicine, The Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Suzuki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Hideo
authors.initials: H
authors.lastname: Ema
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D053148:Caspase 3 / Q000032:analysis; D006412:Hematopoietic Stem Cells / Q000502:physiology* / Q000528:radiation effects; D006657:Histones / Q000032:analysis; D006706:Homeostasis; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000502:physiology*; D011836:Radiation Tolerance; D051020:bcl-X Protein / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494812:Bcl2l1 protein, mouse; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; D011506:Proteins; D051020:bcl-X Protein; C475961:gamma-H2AX protein, mouse; D053148:Caspase 3