| Abstract: |
Williams et al. identify mediators of the amino acid response pathway in leukemia and demonstrate that ZBTB1 is necessary for cellular proliferation specifically under asparagine deprivation. ZBTB1 associates with the promoter of ASNS and promotes the transcriptional upregulation of ASNS under asparagine deprivation. Loss of ZBTB1 sensitizes leukemic cells to L-asparaginase treatment in vitro and in vivo. © 2020 Elsevier Inc. Activating transcription factor 4 (ATF4) is a master transcriptional regulator of the integrated stress response (ISR) that enables cell survival under nutrient stress. The mechanisms by which ATF4 couples metabolic stresses to specific transcriptional outputs remain unknown. Using functional genomics, we identified transcription factors that regulate the responses to distinct amino acid deprivation conditions. While ATF4 is universally required under amino acid starvation, our screens yielded a transcription factor, Zinc Finger and BTB domain-containing protein 1 (ZBTB1), as uniquely essential under asparagine deprivation. ZBTB1 knockout cells are unable to synthesize asparagine due to reduced expression of asparagine synthetase (ASNS), the enzyme responsible for asparagine synthesis. Mechanistically, ZBTB1 binds to the ASNS promoter and promotes ASNS transcription. Finally, loss of ZBTB1 sensitizes therapy-resistant T cell leukemia cells to L-asparaginase, a chemotherapeutic that depletes serum asparagine. Our work reveals a critical regulator of the nutrient stress response that may be of therapeutic value. © 2020 Elsevier Inc. |
