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SMAD4 binds HOXA9 in the cytoplasm and protects primitive hematopoietic cells against nuclear activation by HOXA9 and leukemia transformation.

Quere, Ronan LU ; Karlsson, Göran LU ; Hertwig, Falk LU ; Rissler, Marianne LU ; Lindqvist, Beata LU ; Fioretos, Thoas LU ; Vandenberghe, Peter; Slovak, Marilyn L; Cammenga, Jörg LU and Karlsson, Stefan LU (2011) In Blood 117. p.5918-5930
Abstract
We studied leukemic stem cells (LSCs) in a Smad4(-/-) mouse model of acute myelogenous leukemia (AML) induced either by the HOXA9 gene or by the fusion oncogene NUP98-HOXA9. While HOXA9-SMAD4 complexes accumulate in the cytoplasm of normal hematopoietic stem- and progenitor cells (HSPCs) transduced with these oncogenes, there is no cytoplasmic accumulation of HOXA9 in Smad4(-/-) HSPCs and as a consequence increased levels of HOXA9 accumulate in the nucleus leading to increased immortalization in vitro. Loss of Smad4 accelerates the development of leukemia in vivo due to an increase in transformation of HSPCs. Therefore, the cytoplasmic binding of HOXA9 by SMAD4 is a mechanism to protect HOXA9-induced transformation of normal HSPCs. Since... (More)
We studied leukemic stem cells (LSCs) in a Smad4(-/-) mouse model of acute myelogenous leukemia (AML) induced either by the HOXA9 gene or by the fusion oncogene NUP98-HOXA9. While HOXA9-SMAD4 complexes accumulate in the cytoplasm of normal hematopoietic stem- and progenitor cells (HSPCs) transduced with these oncogenes, there is no cytoplasmic accumulation of HOXA9 in Smad4(-/-) HSPCs and as a consequence increased levels of HOXA9 accumulate in the nucleus leading to increased immortalization in vitro. Loss of Smad4 accelerates the development of leukemia in vivo due to an increase in transformation of HSPCs. Therefore, the cytoplasmic binding of HOXA9 by SMAD4 is a mechanism to protect HOXA9-induced transformation of normal HSPCs. Since Smad4 is a potent tumor suppressor involved in growth control, we developed a strategy to modify the subcellular distribution of SMAD4. We successfully disrupted the interaction between HOXA9 and SMAD4 to activate the TGF-beta pathway and apoptosis, leading to a loss of LSCs. Together, these findings reveal a major role for Smad4 in the negative regulation of leukemia initiation and maintenance induced by HOXA9/NUP98-HOXA9 and provide strong evidence that antagonizing SMAD4 stabilization by these oncoproteins might be a promising novel therapeutic approach in leukemia. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
117
pages
5918 - 5930
publisher
American Society of Hematology
external identifiers
  • wos:000291203200020
  • pmid:21471525
  • scopus:79957976682
ISSN
1528-0020
DOI
10.1182/blood-2010-08-301879
language
English
LU publication?
yes
id
7b3da636-bef5-4a01-8757-d550d46056ef (old id 1937387)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21471525?dopt=Abstract
date added to LUP
2011-05-02 11:10:28
date last changed
2017-03-23 14:02:42
@article{7b3da636-bef5-4a01-8757-d550d46056ef,
  abstract     = {We studied leukemic stem cells (LSCs) in a Smad4(-/-) mouse model of acute myelogenous leukemia (AML) induced either by the HOXA9 gene or by the fusion oncogene NUP98-HOXA9. While HOXA9-SMAD4 complexes accumulate in the cytoplasm of normal hematopoietic stem- and progenitor cells (HSPCs) transduced with these oncogenes, there is no cytoplasmic accumulation of HOXA9 in Smad4(-/-) HSPCs and as a consequence increased levels of HOXA9 accumulate in the nucleus leading to increased immortalization in vitro. Loss of Smad4 accelerates the development of leukemia in vivo due to an increase in transformation of HSPCs. Therefore, the cytoplasmic binding of HOXA9 by SMAD4 is a mechanism to protect HOXA9-induced transformation of normal HSPCs. Since Smad4 is a potent tumor suppressor involved in growth control, we developed a strategy to modify the subcellular distribution of SMAD4. We successfully disrupted the interaction between HOXA9 and SMAD4 to activate the TGF-beta pathway and apoptosis, leading to a loss of LSCs. Together, these findings reveal a major role for Smad4 in the negative regulation of leukemia initiation and maintenance induced by HOXA9/NUP98-HOXA9 and provide strong evidence that antagonizing SMAD4 stabilization by these oncoproteins might be a promising novel therapeutic approach in leukemia.},
  author       = {Quere, Ronan and Karlsson, Göran and Hertwig, Falk and Rissler, Marianne and Lindqvist, Beata and Fioretos, Thoas and Vandenberghe, Peter and Slovak, Marilyn L and Cammenga, Jörg and Karlsson, Stefan},
  issn         = {1528-0020},
  language     = {eng},
  pages        = {5918--5930},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {SMAD4 binds HOXA9 in the cytoplasm and protects primitive hematopoietic cells against nuclear activation by HOXA9 and leukemia transformation.},
  url          = {http://dx.doi.org/10.1182/blood-2010-08-301879},
  volume       = {117},
  year         = {2011},
}