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 Quinn; 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 Quinn, Sten Eirik W Jacobsen

Research output: Contribution to journal › Article › peer-review

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)

Original language	English
Pages (from-to)	3613-3621
Journal	Blood
Volume	118
Issue number	13
DOIs	https://doi.org/10.1182/blood-2010-06-289207
Publication status	Published - 2011

Bibliographical note

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Stem Cell Center (013041110), Hematology/Transplantation (013022014), Experimental Clinical Chemistry (013016010)

Subject classification (UKÄ)

Hematology

UN SDGs

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

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10.1182/blood-2010-06-289207

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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 Quinn, E., & Jacobsen, S. E. W. (2011). Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation. Blood, 118(13), 3613-3621. https://doi.org/10.1182/blood-2010-06-289207

@article{176cf1cca5194061bb23e3fa53bb9f31,

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. (Blood. 2011; 118(13):3613-3621)",

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 {Sitnicka Quinn}, Ewa and Jacobsen, {Sten Eirik W}",

note = "The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Stem Cell Center (013041110), Hematology/Transplantation (013022014), Experimental Clinical Chemistry (013016010)",

year = "2011",

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

language = "English",

volume = "118",

pages = "3613--3621",

journal = "Blood",

issn = "1528-0020",

publisher = "American Society of Hematology",

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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 Quinn, E & Jacobsen, SEW 2011, 'Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation', Blood, vol. 118, no. 13, pp. 3613-3621. https://doi.org/10.1182/blood-2010-06-289207

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 Quinn, Ewa

AU - Jacobsen, Sten Eirik W

N1 - The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Stem Cell Center (013041110), Hematology/Transplantation (013022014), Experimental Clinical Chemistry (013016010)

PY - 2011

Y1 - 2011

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. (Blood. 2011; 118(13):3613-3621)

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. (Blood. 2011; 118(13):3613-3621)

U2 - 10.1182/blood-2010-06-289207

DO - 10.1182/blood-2010-06-289207

M3 - Article

C2 - 21813452

SN - 1528-0020

VL - 118

SP - 3613

EP - 3621

JO - Blood

JF - Blood

IS - 13

ER -

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

Abstract

Bibliographical note

Subject classification (UKÄ)

UN SDGs

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