Nie DY*, Tabor JR*, Li J, Kutera M, St-Germain J, Hanley RP, Wolf EZ, Paulakonis E, Kenney TMG, Duan S, Shrestha S, Owens DDG, Pon A, Szewczyk M, Lamberto AJ, Menes M, Li F, Barsyte-Lovejoy D, Brown NG, Barsotti AM, Stamford AW, Collins JL, Wilson DJ, Raught B, Licht J, James L, Arrowsmith C. Recruitment of FBXO22 for Targeted Degradation of NSD2. Nature Chemical Biology. 2024 Jul 4. Online ahead of print.

In our collaboration, based upon targeted protein degradation (TPD), we developed and characterized a novel NSD2 degrader UNC8732, which facilitates FBXO22-mediated degradation of NSD2 in acute lymphoblastic leukemia cells harboring the NSD2 gain-of-function mutation p.E1099K, resulting in growth suppression, apoptosis, and reversal of drug resistance. We present a potent NSD2 degrader for the exploration of NSD2 disease phenotypes, which could be moved to clinical trials for NSD2 mutation-driven cancers. 

Li J, Hlavka-Zhang J, Shrimp JH, Piper C, Dupere-Richer D, Roth JS, Jing D, Casellas Roman HL, Troche C, Swaroop A, Kulis M, Oyer JA, Will CM, Shen M, Riva A, Bennett RL, Ferrando AA, Hall MD, Lock RB, Licht JD. PRC2 inhibitors overcome glucocorticoid resistance driven by NSD2 mutation in pediatric acute lymphoblastic leukemia. Cancer Discovery. 2022; 12(1): 186.

Using CRISPR/Cas9 gene editing, drug screen, multi-omics, and PDX models, we identified that NSD2 p.E1099K mutation specifically drove glucocorticoid (GC) resistance due to the aberrant deposition of H3K27me3 at the NR3C1 promoter in pediatric ALL and contributed to the relapse. Pre-treatment of NSD2 mutant cells or PDX mice with EZH2 inhibitors removed H3K27me3 at NR3C1 promoter and significantly reversed GC resistance. This suggests a novel mechanism of GC resistance and a promising therapeutic approach for relapsed ALL patients with NSD2 mutation, and this has recently been presented to the Children’s Oncology Group as a potential clinical trial. 

Yang H, Kurtenbach S, Guo Y, Lohse I, Durante MA, Li J, Li Z, Al-Ali H, Li L, Chen Z, Field MG, Zhang P, Chen S, Yamamoto S, Li Z, Zhou Y, Nimer SD, Harbour JW, Wahlestedt C, Xu M, Yang FC. Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies. Blood. 2018; 131(3): 328.

With the generation of an Asxl1Y588X transgenic mouse model, we demonstrated that ASXL1aa1-587 has a gain-of-function role in promoting myeloid malignancies and provides a powerful platform to test therapeutic approaches of targeting the ASXL1 truncation mutations in myeloid malignancies. 

Li J*, He F*, Zhang P*, Chen S, Shi H, Sun Y, Guo Y, Yang H, Man N, Greenblatt S, Li Z, Guo Z, Zhou Y, Wang L, Morey L, Williams S, Chen X, Wang QT, Nimer SD, Yu P, Wang QF, Xu M, Yang FC. Loss of Asxl2 leads to myeloid malignancies in mice. Nature Communications. 2017; 8: 15456.

Using a knock-out mouse model, we demonstrated that Asxl2-loss led to the development of MDS-like disease and myeloid leukemia transformation. Deletion of Asxl2 altered histone modification (H3K27ac and H3K4me1/2) and gene expression patterns related to increased long-term hematopoietic stem cells (HSCs) and granulocyte-monocyte progenitors (GMPs), suggesting that ASXL2 functions as a tumor suppressor to maintain normal HSC function.