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Ferrata Storti Foundation
Haematologica 2021 Volume 106(4):1000-1007
Acute Myeloid Leukemia
The ASXL1-G643Wvariant accelerates the development of CEBPA mutant acute myeloid leukemia
Teresa D’Altri,1,2,3 Anna S. Wilhelmson,1,2,3 Mikkel B. Schuster,1,2,3 Anne Wenzel,1,2,3 Adrija Kalvisa,1,2,3 Sachin Pundhir,1,2,3
Anne Meldgaard Hansen1,2,3 and Bo T. Porse1,2,3
1The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen; 2Biotech Research and Innovation Centre (BRIC), University of Copenhagen and 3Danish Stem Cell Center (DanStem) Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
ABSTRACT
ASXL1 is one of the most commonly mutated genes in myeloid malig- nancies, 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 knockin mouse model carrying the most frequent ASXL1 mutation identi- fied in MDS patients, ASXL1 p.G643WfsX12. Mutant mice neither dis- played any major hematopoietic defects nor developed any apparent hema- tological disease. In AML patients, ASXL1 mutations co-occur with muta- tions 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 there- fore constitutes an excellent experimental system for further studies into the clinically important question of chemotherapy resistance mediated by mutant ASXL1.
Introduction
Additional sex comb-like 1 (ASXL1) is a frequently mutated gene in myeloid malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).1,2 Moreover, ASXL1 mutations are also highly prevalent in prema- lignant states such as clonal hematopoiesis of indeterminate potential (CHIP), demonstrating that ASXL1 lesions are early driver events with the potential to pre- dispose for further malignant transformation.3,4 The vast majority of ASXL1 muta- tions are located in the last exon and are deletions, insertions, or substitutions resulting in stop codon mutations and truncation of the ASXL1 protein.1,2 Mutations are always monoallelic and mRNA expression levels are variable. Due to difficulties in detecting ASXL1 in human samples, ASXL1 mutations were original- ly believed to be loss of function lesions and consequently haploinsufficient.5 However, in a more recent work, the truncated protein can indeed be detected, rais- ing the possibility that ASXL1 mutations may act as dominant negative or gain of function variants.6
Mechanistically, ASXL1 is a dual function epigenetic regulator. Specifically, it interacts directly with the BRCA1-associated protein 1 (BAP1) to form a complex which de-ubiquitinates H2AK119Ub, a repressive histone mark deposited by the polycomb repressive complex 1 (PRC1).5,7,8 Moreover, ASXL1 interacts with the components of the polycomb repressive complex 2 (PRC2) which deposits the H3K27me3 repressive mark.5,9
The interest in the role of ASXL1 in malignant hematopoiesis has spurred the development of several Asxl1 knockout mouse models10-12 (for a recent review, see13) Although these models do not result in identical phenotypes, they all show pheno- types consistent with human MDS. Interestingly, overexpression of a truncated form of Asxl1 yielded similar results suggesting that the mutations found in patients
Correspondence:
BO PORSE
bo.porse@finsenlab.dk
Received: August 16, 2019. Accepted: March 19, 2020. Pre-published: May 7, 2020.
https://doi.org/10.3324/haematol.2019.235150
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