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Loss of p53 function compromises the response to many anti\u2010leukemic therapies, underscoring the need for agents that are effective in\n                    <jats:italic>TP53\u2010<\/jats:italic>\n                    deficient cells. Leukemic blasts depend on de novo pyrimidine synthesis to sustain proliferation, and the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) is essential for this pathway. While DHODH inhibitors (DHODHis) show preclinical anti\u2010leukemic activity, the efficacy in\n                    <jats:italic>TP53<\/jats:italic>\n                    \u2010deficient contexts has not been tested. Using both isogenic\n                    <jats:italic>TP53<\/jats:italic>\n                    \u2010wildtype and knock\u2010out cell line models and patient\u2010derived xenografts (PDXs), we show that dual inhibition of DHODH and Ataxia Telangiectasia and Rad3\u2010related (ATR) produces pronounced anti\u2010leukemic effects, irrespective of the\n                    <jats:italic>TP53<\/jats:italic>\n                    status. Through integrated transcriptomic and metabolomic analyses, we show that combined inhibition of DHODH and ATR leads to a reduced flux of glucose into the TCA cycle, accompanied by an increase in oxidative stress. This metabolic phenotype triggers cell death through a mechanism converging on Activating Transcription Factor 4 (ATF4), a key integrator of cellular responses to metabolic and oxidative stress, which operates largely independently of p53. Taken together, our findings identify ATF4\u2010mediated cell death as a previously unrecognized vulnerability in\n                    <jats:italic>TP53<\/jats:italic>\n                    \u2010deficient ALL.\n                  <\/jats:p>","DOI":"10.1002\/hem3.70439","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T17:22:58Z","timestamp":1784568178000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combined inhibition of de novo pyrimidine synthesis and ATR promotes ATF4\u2010mediated cell death in\n                    <i>TP53<\/i>\n                    \u2010deficient ALL"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-5246-1734","authenticated-orcid":false,"given":"Kari J. 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