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Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation

Kharazi, Shabnam LU ; Mead, Adam J.; Mansour, Anna LU ; Hultquist, Anne LU ; Böiers, Charlotta LU ; Luc, Sidinh LU ; Buza-Vidas, Natalija; Ma, Zhi LU ; Ferry, Helen and Atkinson, Debbie, et al. (2011) In Blood 118(13). p.3613-3621
Abstract
Acquisition of homozygous activating growth factor receptor mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knockin model of Flt3-internal tandem duplication (Flt3-ITD)-induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin(-)Sca1(+)c-Kit(+) progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild-type allele. Further,... (More)
Acquisition of homozygous activating growth factor receptor mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knockin model of Flt3-internal tandem duplication (Flt3-ITD)-induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin(-)Sca1(+)c-Kit(+) progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild-type allele. Further, whereas autocrine FLT3 ligand production has been implicated in FLT3-ITD myeloid malignancies and resistance to FLT3 inhibitors, we demonstrate here that the mouse Flt3(ITD/ITD) myeloid phenotype is FLT3 ligand-independent. (Blood. 2011; 118(13):3613-3621) (Less)
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type
Contribution to journal
publication status
published
subject
in
Blood
volume
118
issue
13
pages
3613 - 3621
publisher
American Society of Hematology
external identifiers
  • wos:000295359300027
  • pmid:21813452
  • scopus:80053348990
ISSN
1528-0020
DOI
10.1182/blood-2010-06-289207
language
English
LU publication?
yes
id
176cf1cc-a519-4061-bb23-e3fa53bb9f31 (old id 2179667)
date added to LUP
2011-11-01 07:53:47
date last changed
2017-08-27 03:24:06
@article{176cf1cc-a519-4061-bb23-e3fa53bb9f31,
  abstract     = {Acquisition of homozygous activating growth factor receptor mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knockin model of Flt3-internal tandem duplication (Flt3-ITD)-induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin(-)Sca1(+)c-Kit(+) progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild-type allele. Further, whereas autocrine FLT3 ligand production has been implicated in FLT3-ITD myeloid malignancies and resistance to FLT3 inhibitors, we demonstrate here that the mouse Flt3(ITD/ITD) myeloid phenotype is FLT3 ligand-independent. (Blood. 2011; 118(13):3613-3621)},
  author       = {Kharazi, Shabnam and Mead, Adam J. and Mansour, Anna and Hultquist, Anne and Böiers, Charlotta and Luc, Sidinh and Buza-Vidas, Natalija and Ma, Zhi and Ferry, Helen and Atkinson, Debbie and Reckzeh, Kristian and Masson, Kristina and Cammenga, Jörg and Rönnstrand, Lars and Arai, Fumio and Suda, Toshio and Nerlov, Claus and Sitnicka Quinn, Ewa and Jacobsen, Sten Eirik W},
  issn         = {1528-0020},
  language     = {eng},
  number       = {13},
  pages        = {3613--3621},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation},
  url          = {http://dx.doi.org/10.1182/blood-2010-06-289207},
  volume       = {118},
  year         = {2011},
}