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<p>Relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) remains a leading cause of cancer-related death in children and young adults. While CD19-directed chimeric antigen receptor T cell (CAR-T) therapy offers promise, high rates of long-term failure underscore the need to understand resistance mechanisms. Our studies found p53 inactivation promotes CAR-T resistance in human pre-B-ALL cell lines. Through genome-wide CRISPR/Cas9 screening of CAR-sensitive <i>TP53</i>-wildtype and CAR-resistant <i>TP53</i>-mutated CD19 + B-ALL cell lines, we found the Fatty Acid Transport Protein 2 (FATP2, encoded by <i>SLC27A2</i>) is a leukemia-intrinsic mechanism of CAR-T resistance in <i>TP53</i>-mutant B-ALL. High <i>SLC27A2</i> expression in pediatric B-ALL patients correlate with worse survival outcomes following conventional chemotherapy. Using B-ALL cell lines and patient-derived xenografts, we show that FATP2-expressing <i>TP53</i>-mutant B-ALL resistance to CAR-T is dependent on exogenous lipid uptake to fuel fatty acid oxidation (FAO) and cell survival, which can be pharmacologically targeted through inhibition of neutral lipolysis and CPT1. These findings identify FATP2-mediated fatty acid uptake and downstream FAO as a potential target to improve existing CAR-T efficacy in human B-ALL.</p>

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FATP2-mediated lipid metabolism enhances chimeric antigen receptor T-cell therapy resistance in B-cell acute lymphoblastic leukemia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月30日

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  • Clarissa Garcia,
  • Kaylyn U. Lyons,
  • Julian Grandvallet Contreras,
  • Tian Liu,
  • Alexis J. Donnelly,
  • Amanda J. Novak,
  • Amy Argabright,
  • Colin Anderson,
  • Abby Grier,
  • Sabrina Smith,
  • Joshua Michlin,
  • Jesutomisin Olusoji,
  • Railey G. Mikeska,
  • Xin Zhou,
  • Huimin Geng,
  • Jeremy T. Rahkola,
  • Hiten N. Patel,
  • Jeffrey G. Jacot,
  • Markus Müschen,
  • Angelo D’Alessandro,
  • John E. Dick,
  • Ilaria Iacobucci,
  • Charles G. Mullighan,
  • Julie A. Reisz,
  • Tzu Phang,
  • M. Eric Kohler,
  • Matthew T. Witkowski

摘要

Relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) remains a leading cause of cancer-related death in children and young adults. While CD19-directed chimeric antigen receptor T cell (CAR-T) therapy offers promise, high rates of long-term failure underscore the need to understand resistance mechanisms. Our studies found p53 inactivation promotes CAR-T resistance in human pre-B-ALL cell lines. Through genome-wide CRISPR/Cas9 screening of CAR-sensitive TP53-wildtype and CAR-resistant TP53-mutated CD19 + B-ALL cell lines, we found the Fatty Acid Transport Protein 2 (FATP2, encoded by SLC27A2) is a leukemia-intrinsic mechanism of CAR-T resistance in TP53-mutant B-ALL. High SLC27A2 expression in pediatric B-ALL patients correlate with worse survival outcomes following conventional chemotherapy. Using B-ALL cell lines and patient-derived xenografts, we show that FATP2-expressing TP53-mutant B-ALL resistance to CAR-T is dependent on exogenous lipid uptake to fuel fatty acid oxidation (FAO) and cell survival, which can be pharmacologically targeted through inhibition of neutral lipolysis and CPT1. These findings identify FATP2-mediated fatty acid uptake and downstream FAO as a potential target to improve existing CAR-T efficacy in human B-ALL.