title: The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease.
abstract: The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced a gene signature associated with hematopoietic stem cells and myeloid differentiation, as well as hepatocyte growth factor signaling. Here we demonstrate that, in contrast to what has generally been assumed, the significant impact of SKI on hematopoiesis is independent of its ability to inhibit TGF-beta signaling. Instead, myeloid progenitors expressing SKI are partially dependent on functional hepatocyte growth factor signaling. Collectively our results demonstrate that SKI is an important regulator of hematopoietic stem cell activity and its overexpression leads to myeloproliferative disease.
authors.affiliation: sofie.singbrant@med.lu.se.
authors.forename: Sofie
authors.initials: S
authors.lastname: Singbrant
authors.forename: Meaghan
authors.initials: M
authors.lastname: Wall
authors.forename: Jennifer
authors.initials: J
authors.lastname: Moody
authors.forename: Göran
authors.initials: G
authors.lastname: Karlsson
authors.forename: Alistair M
authors.initials: AM
authors.lastname: Chalk
authors.forename: Brian
authors.initials: B
authors.lastname: Liddicoat
authors.forename: Megan R
authors.initials: MR
authors.lastname: Russell
authors.forename: Carl R
authors.initials: CR
authors.lastname: Walkley
authors.forename: Stefan
authors.initials: S
authors.lastname: Karlsson
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004920:Erythropoiesis / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D038041:Lymphopoiesis / Q000235:genetics; D051379:Mice; D038042:Myelopoiesis / Q000235:genetics; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; C060614:SKI protein, human; D017228:Hepatocyte Growth Factor