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The ASXL1-G643W variant accelerates the development of CEBPA mutant acute myeloid leukemia

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@article{787a2318c4e4425595153ea8799f7c2f,
title = "The ASXL1-G643W variant accelerates the development of CEBPA mutant acute myeloid leukemia",
abstract = "ASXL1 is one of the most commonly mutated genes in myeloid malignancies, including Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). In order to further our understanding of the role of ASXL1 lesions in malignant hematopoiesis, we generated a novel knock-in mouse model carrying the most frequent ASXL1 mutation identified in MDS patients, p.G643WfsX12. Mutant mice did not display any major hematopoietic defects nor developed any apparent hematological disease. In AML patients, ASXL1 mutations co-occur with mutations in CEBPA and we therefore generated compound Cebpa and Asxl1 mutated mice. Using a transplantation model, we found that the mutated Asxl1 allele significantly accelerated disease development in a CEBPA mutant context. Importantly, we demonstrated that, similar to the human setting, Asxl1 mutated mice responded poorly to chemotherapy. This model therefore constitutes an excellent experimental system for further studies into the clinically important question of chemotherapy resistance mediated by mutant ASXL1.",
author = "Teresa D'Altri and Wilhelmson, {Anna S} and Schuster, {Mikkel B} and Anne Wenzel and Adrija Kalvisa and Sachin Pundhir and Hansen, {Anne Meldgaard} and Porse, {Bo T}",
note = "Copyright {\circledC} 2020, Ferrata Storti Foundation.",
year = "2020",
month = "5",
day = "7",
doi = "10.3324/haematol.2019.235150",
language = "English",
journal = "Haematologica",
issn = "0390-6078",
publisher = "Fondazione/Ferrata Storti",

}

RIS

TY - JOUR

T1 - The ASXL1-G643W variant accelerates the development of CEBPA mutant acute myeloid leukemia

AU - D'Altri, Teresa

AU - Wilhelmson, Anna S

AU - Schuster, Mikkel B

AU - Wenzel, Anne

AU - Kalvisa, Adrija

AU - Pundhir, Sachin

AU - Hansen, Anne Meldgaard

AU - Porse, Bo T

N1 - Copyright © 2020, Ferrata Storti Foundation.

PY - 2020/5/7

Y1 - 2020/5/7

N2 - ASXL1 is one of the most commonly mutated genes in myeloid malignancies, including Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). In order to further our understanding of the role of ASXL1 lesions in malignant hematopoiesis, we generated a novel knock-in mouse model carrying the most frequent ASXL1 mutation identified in MDS patients, p.G643WfsX12. Mutant mice did not display any major hematopoietic defects nor developed any apparent hematological disease. In AML patients, ASXL1 mutations co-occur with mutations in CEBPA and we therefore generated compound Cebpa and Asxl1 mutated mice. Using a transplantation model, we found that the mutated Asxl1 allele significantly accelerated disease development in a CEBPA mutant context. Importantly, we demonstrated that, similar to the human setting, Asxl1 mutated mice responded poorly to chemotherapy. This model therefore constitutes an excellent experimental system for further studies into the clinically important question of chemotherapy resistance mediated by mutant ASXL1.

AB - ASXL1 is one of the most commonly mutated genes in myeloid malignancies, including Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). In order to further our understanding of the role of ASXL1 lesions in malignant hematopoiesis, we generated a novel knock-in mouse model carrying the most frequent ASXL1 mutation identified in MDS patients, p.G643WfsX12. Mutant mice did not display any major hematopoietic defects nor developed any apparent hematological disease. In AML patients, ASXL1 mutations co-occur with mutations in CEBPA and we therefore generated compound Cebpa and Asxl1 mutated mice. Using a transplantation model, we found that the mutated Asxl1 allele significantly accelerated disease development in a CEBPA mutant context. Importantly, we demonstrated that, similar to the human setting, Asxl1 mutated mice responded poorly to chemotherapy. This model therefore constitutes an excellent experimental system for further studies into the clinically important question of chemotherapy resistance mediated by mutant ASXL1.

U2 - 10.3324/haematol.2019.235150

DO - 10.3324/haematol.2019.235150

M3 - Journal article

JO - Haematologica

JF - Haematologica

SN - 0390-6078

ER -

ID: 60067627