TY - JOUR
T1 - Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation
AU - Kharazi, Shabnam
AU - Mead, Adam J.
AU - Mansour, Anna
AU - Hultquist, Anne
AU - Böiers, Charlotta
AU - Luc, Sidinh
AU - Buza-Vidas, Natalija
AU - Ma, Zhi
AU - Ferry, Helen
AU - Atkinson, Debbie
AU - Reckzeh, Kristian
AU - Masson, Kristina
AU - Cammenga, Jörg
AU - Rönnstrand, Lars
AU - Arai, Fumio
AU - Suda, Toshio
AU - Nerlov, Claus
AU - Sitnicka, Ewa
AU - Jacobsen, Sten Eirik W.
PY - 2011/9/29
Y1 - 2011/9/29
N2 - 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 Flt3ITD/ITD myeloid phenotype is FLT3 ligand-independent.
AB - 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 Flt3ITD/ITD myeloid phenotype is FLT3 ligand-independent.
UR - http://www.scopus.com/inward/record.url?scp=80053348990&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053348990&partnerID=8YFLogxK
U2 - 10.1182/blood-2010-06-289207
DO - 10.1182/blood-2010-06-289207
M3 - Article
C2 - 21813452
AN - SCOPUS:80053348990
SN - 0006-4971
VL - 118
SP - 3613
EP - 3621
JO - Blood
JF - Blood
IS - 13
ER -
