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

Shabnam Kharazi; Adam J. Mead; Anna Mansour; Anne Hultquist; Charlotta Böiers; Sidinh Luc; Natalija Buza-Vidas; Zhi Ma; Helen Ferry; Debbie Atkinson; Kristian Reckzeh; Kristina Masson; Jörg Cammenga; Lars Rönnstrand; Fumio Arai; Toshio Suda; Claus Nerlov; Ewa Sitnicka; Sten Eirik W. Jacobsen

doi:10.1182/blood-2010-06-289207

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

Shabnam Kharazi, Adam J. Mead, Anna Mansour, Anne Hultquist, Charlotta Böiers, Sidinh Luc, Natalija Buza-Vidas, Zhi Ma, Helen Ferry, Debbie Atkinson, Kristian Reckzeh, Kristina Masson, Jörg Cammenga, Lars Rönnstrand, Fumio Arai, Toshio Suda, Claus Nerlov, Ewa Sitnicka, Sten Eirik W. Jacobsen

24 Citations (Scopus)

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.

Original language	English
Journal	Blood
Pages (from-to)	3613-3621
Number of pages	9
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood-2010-06-289207
Publication status	Published - 29 Sept 2011
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1182/blood-2010-06-289207

Cite this

Kharazi, S., Mead, A. J., Mansour, A., Hultquist, A., Böiers, C., Luc, S., Buza-Vidas, N., Ma, Z., Ferry, H., Atkinson, D., Reckzeh, K., Masson, K., Cammenga, J., Rönnstrand, L., Arai, F., Suda, T., Nerlov, C., Sitnicka, E., & Jacobsen, S. E. W. (2011). Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation. Blood, 3613-3621. https://doi.org/10.1182/blood-2010-06-289207

Kharazi, S, Mead, AJ, Mansour, A, Hultquist, A, Böiers, C, Luc, S, Buza-Vidas, N, Ma, Z, Ferry, H, Atkinson, D, Reckzeh, K, Masson, K, Cammenga, J, Rönnstrand, L, Arai, F, Suda, T, Nerlov, C, Sitnicka, E & Jacobsen, SEW 2011, 'Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation', Blood, pp. 3613-3621. https://doi.org/10.1182/blood-2010-06-289207

@article{87cce9ef0a6c49ca88a9be81a077aaec,

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

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.",

author = "Shabnam Kharazi and Mead, {Adam J.} and Anna Mansour and Anne Hultquist and Charlotta B{\"o}iers and Sidinh Luc and Natalija Buza-Vidas and Zhi Ma and Helen Ferry and Debbie Atkinson and Kristian Reckzeh and Kristina Masson and J{\"o}rg Cammenga and Lars R{\"o}nnstrand and Fumio Arai and Toshio Suda and Claus Nerlov and Ewa Sitnicka and Jacobsen, {Sten Eirik W.}",

year = "2011",

month = sep,

day = "29",

doi = "10.1182/blood-2010-06-289207",

language = "English",

pages = "3613--3621",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

}

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 Flt3(ITD/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 Flt3(ITD/ITD) myeloid phenotype is FLT3 ligand-independent.

U2 - 10.1182/blood-2010-06-289207

DO - 10.1182/blood-2010-06-289207

M3 - Journal article

C2 - 21813452

SN - 0006-4971

SP - 3613

EP - 3621

JO - Blood

JF - Blood

ER -

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

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this