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The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease

Singbrant, Sofie LU ; Wall, Meaghan; Moody, Jennifer LU ; Karlsson, Göran LU ; Chalk, Alistair M.; Liddicoat, Brian; Russell, Megan R.; Walkley, Carl R. and Karlsson, Stefan LU (2014) In Haematologica 99(4). p.647-655
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,... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Haematologica
volume
99
issue
4
pages
647 - 655
publisher
Ferrata Storti Foundation
external identifiers
  • wos:000336256100015
  • scopus:84897380679
ISSN
1592-8721
DOI
10.3324/haematol.2013.093971
language
English
LU publication?
yes
id
eb1621e2-b687-4666-81af-4bd9e02e1c64 (old id 4470194)
date added to LUP
2014-07-01 07:40:03
date last changed
2017-03-23 08:54:47
@article{eb1621e2-b687-4666-81af-4bd9e02e1c64,
  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.},
  author       = {Singbrant, Sofie and Wall, Meaghan and Moody, Jennifer and Karlsson, Göran and Chalk, Alistair M. and Liddicoat, Brian and Russell, Megan R. and Walkley, Carl R. and Karlsson, Stefan},
  issn         = {1592-8721},
  language     = {eng},
  number       = {4},
  pages        = {647--655},
  publisher    = {Ferrata Storti Foundation},
  series       = {Haematologica},
  title        = {The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease},
  url          = {http://dx.doi.org/10.3324/haematol.2013.093971},
  volume       = {99},
  year         = {2014},
}