The ASXL1-G643W variant accelerates the development of CEBPA mutant acute myeloid leukemia
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The ASXL1-G643W variant accelerates the development of CEBPA mutant acute myeloid leukemia. / D'Altri, Teresa; Wilhelmson, Anna S; Schuster, Mikkel B; Wenzel, Anne; Kalvisa, Adrija; Pundhir, Sachin; Hansen, Anne Meldgaard; Porse, Bo T.
In: Haematologica, Vol. 106, No. 4, 2021, p. 1000-1007.Research output: Contribution to journal › Journal article › Research › peer-review
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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 - 2021
Y1 - 2021
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
C2 - 32381577
VL - 106
SP - 1000
EP - 1007
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 4
ER -
ID: 246736447