Asxl2, an epigenetic regulator, is a transcription regulator and a member of the ETP family. It is involved in multiple biological pathways. It interacts with PPARγ and is crucial for maintaining normal hematopoiesis, glucose, lipid, and skeletal homeostasis [1,3,4]. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, have been instrumental in studying its functions.

In KO mouse models, Asxl2 -/- mice exhibit insulin resistance, lipodystrophy, and severe osteopetrosis due to failed osteoclast differentiation [3]. Myeloid-specific deletion of Asxl2 (Asxl2ΔLysM) in mice makes them resistant to diet-induced weight gain, with protected energy expenditure and brown adipose tissue metabolism [2]. Loss of Asxl2 in mice also leads to myeloid malignancies like myelodysplastic syndrome (MDS)-like disease, with increased self-renewal of hematopoietic stem cells (HSCs) [7]. In addition, in acute myeloid leukemia (AML) patients with t(8;21), truncating alterations in ASXL2 are frequently identified, and ASXL2 deficiency in mouse models promotes myeloid expansion [5,6].

In conclusion, Asxl2 is a master regulator of skeletal, lipid, and glucose homeostasis and is essential for normal hematopoiesis. Mouse models with Asxl2 KO or CKO have revealed its role in obesity, metabolic homeostasis, and myeloid malignancies, providing valuable insights into the mechanisms underlying these disease conditions.

References:

1. Li, Mengru, Xu, Lijun, Zhang, Rui, Dong, Chunming. . Epigenetic Regulator ASXL2: Structure, Function and its Predictive Value in Diseases. In Current protein & peptide science, 24, 22-30. doi:10.2174/1389203724666221208103516. https://pubmed.ncbi.nlm.nih.gov/36503466/

2. Zou, Wei, Rohatgi, Nidhi, Brestoff, Jonathan R, Abumrad, Nada A, Teitelbaum, Steven L. . Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditure. In The Journal of clinical investigation, 130, 2644-2656. doi:10.1172/JCI128687. https://pubmed.ncbi.nlm.nih.gov/32310225/

3. Izawa, Takashi, Rohatgi, Nidhi, Fukunaga, Tomohiro, Teitelbaum, Steven L, Zou, Wei. 2015. ASXL2 Regulates Glucose, Lipid, and Skeletal Homeostasis. In Cell reports, 11, 1625-37. doi:10.1016/j.celrep.2015.05.019. https://pubmed.ncbi.nlm.nih.gov/26051940/

4. Micol, Jean-Baptiste, Pastore, Alessandro, Inoue, Daichi, Preudhomme, Claude, Abdel-Wahab, Omar. 2017. ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia. In Nature communications, 8, 15429. doi:10.1038/ncomms15429. https://pubmed.ncbi.nlm.nih.gov/28516957/

5. Madan, Vikas, Han, Lin, Hattori, Norimichi, Wang, Q Tian, Koeffler, H Phillip. 2018. ASXL2 regulates hematopoiesis in mice and its deficiency promotes myeloid expansion. In Haematologica, 103, 1980-1990. doi:10.3324/haematol.2018.189928. https://pubmed.ncbi.nlm.nih.gov/30093396/

6. Zhang, Xiang, Jin, Jie, Yu, Wenjuan. . ASXL2 mutation is recurrent in non-de novo AML1-ETO-negative acute myeloid leukemia. In Annals of hematology, 98, 2621-2623. doi:10.1007/s00277-019-03804-w. https://pubmed.ncbi.nlm.nih.gov/31637484/

7. Li, Jianping, He, Fuhong, Zhang, Peng, Xu, Mingjiang, Yang, Feng-Chun. 2017. Loss of Asxl2 leads to myeloid malignancies in mice. In Nature communications, 8, 15456. doi:10.1038/ncomms15456. https://pubmed.ncbi.nlm.nih.gov/28593990/