Citations 2
Direct pharmacological targeting of asparagine synthetase to overcome resistance to L-asparaginase in ALL therapy
Claude, Rodney, Srivastava, Sankalp , Staschke, Kirk A., Fritz, Carlos A. Mellado, Chen, Shaoxiong, Liu, Lei, Zhong, Minghua, Lanman, Nadia A, Davé, Utpal P. , Batra, Sandeep , Zhou, Jiehao , Fang, Yue, Zhang, C , Kapur, Reuben , Wek, Ronald C., Zhang, Ji , Staschke, Kirk A. , Fritz, Carlos Mellado , Zhong, Minghua, Kothandaraman, Harish , Lanman, Nadia A. , Fan, Jing , Wek, Ronald C. , Zhang, Ji
JCI Insight | June 4, 2026 | Volume: 11 | Issue: 14 | Pages: No page available
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from both B and T cell lineages (B-ALL and T-ALL). Current therapy exploits ALL cells’ low expression of asparagine synthetase (ASNS) by using L-asparaginase, a bacterial enzyme that depletes circulating asparagine. However, resistance can emerge through induction of ASNS, mediated in part by the amino acid stress sensor GCN2. In this study, we addressed the efficacy of L-asparaginase in combination with genetic or pharmacological inhibition of GCN2 and the ASNS inhibitor ASX-173. Using a Kras G12D -driven mouse model of T-ALL, we found that GCN2 is dispensable for leukemogenesis. However, genetic inactivation or pharmacologic inhibition of GCN2 sensitized ALL cells to asparagine depletion, correlating with impaired ASNS induction. While GCN2 targeting enhanced sensitivity to asparagine depletion, a subset of Gcn2 –/– T-ALL cells retained high ASNS expression and remained resistant to L-asparaginase. Likewise, some human T-ALL cells with elevated ASNS levels were refractory to GCN2 inhibition even under asparagine-depleted conditions. When combined with L-asparaginase, ASX-173 effectively eliminated ASNS hi leukemic cells in vitro and in vivo. These findings suggest that direct targeting of ASNS provides therapeutic benefit in leukemias that express high levels of ASNS and are resistant to GCN2 inhibition under asparagine-depleted conditions.
An IL-9–pulmonary macrophage axis defines the allergic lung inflammatory environment
Fu, Yongyao , Wang, Jocelyn , Zhou, Baohua , Pajulas, Abigail , Gao, Hongyu , Ramdas, Baskar , Koh, Byunghee , Ulrich, Benjamin J. , Yang, Shuangshuang , Kapur, Reuben , Licona-Limón, Paula , Takatsuka, Shogo , Kitamura, Daisuke , Kaplan, Mark H. , Renauld, Jean-Christophe , Paczesny, Sophie , Liu, Yunlong , Tighe, Robert M , Licona-Limón, Paula , Flavell, Richard A , Takatsuka, Shogo , Tepper, Robert S , Sun, Jie , Kaplan, Mark H , Tighe, Robert M. , Flavell, Richard A. , Sun, Jie
Science Immunology | February 18, 2022 | Volume: 7 | Issue: 68 | Pages: No page available
Despite IL-9 functioning as a pleiotropic cytokine in mucosal environments, the IL-9–responsive cell repertoire is still not well defined. Here, we found that IL-9 mediates proallergic activities in the lungs by targeting lung macrophages. IL-9 inhibits alveolar macrophage expansion and promotes recruitment of monocytes that develop into CD11c + and CD11c − interstitial macrophage populations. Interstitial macrophages were required for IL-9–dependent allergic responses. Mechanistically, IL-9 affected the function of lung macrophages by inducing Arg1 activity. Compared with Arg1-deficient lung macrophages, Arg1-expressing macrophages expressed greater amounts of CCL5. Adoptive transfer of Arg1 + lung macrophages but not Arg1 − lung macrophages promoted allergic inflammation that Il9r −/− mice were protected against. In parallel, the elevated expression of IL-9, IL-9R, Arg1, and CCL5 was correlated with disease in patients with asthma. Thus, our study uncovers an IL-9/macrophage/Arg1 axis as a potential therapeutic target for allergic airway inflammation.