JAK2, complemented by a second signal from c-kit or flt-3, triggers extensive self-renewal of primary multipotential hemopoietic cells.
Defining signals that can support the self-renewal of multipotential hemopoietic progenitor cells (MHPCs) is pertinent to understanding leukemogenesis and may be relevant to developing stem cell-based therapies. Here we define a set of signals, JAK2 plus either c-kit or flt-3, which together can support extensive MHPC self-renewal. Phenotypically and functionally distinct populations of MHPCs were obtained, depending on which receptor tyrosine kinase, c-kit or flt-3, was activated. Self-renewal was abrogated in the absence of STAT5a/b, and in the presence of inhibitors targeting either the mitogen-activated protein kinase or phosphatidylinositol 3' kinase pathways. These findings suggest that a simple two-component signal can drive MHPC self-renewal.
Zhao
Shengming
S
Division of Hematology, University of Washington, Seattle, WA, USA.
Zoller
Karen
K
Masuko
Masayoshi
M
Rojnuckarin
Ponlapat
P
Yang
Xuexian O
XO
Parganas
Evan
E
Kaushansky
Kenneth
K
Ihle
James N
JN
Papayannopoulou
Thalia
T
Willerford
Dennis M
DM
Clackson
Tim
T
Blau
C Anthony
CA
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D053614:Janus Kinase 2; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D051941:fms-Like Tyrosine Kinase 3
D011518:Proto-Oncogene Proteins; C497971:Flt3 protein, mouse; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2