FATP2-mediated lipid metabolism enhances chimeric antigen receptor T-cell therapy resistance in B-cell acute lymphoblastic leukemia
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.
Authors
- Jeffrey G. Jacot (ORCID: https://orcid.org/0000-0002-1272-5055)
- Jeremy Rahkola
- Huimin Geng (ORCID: https://orcid.org/0000-0001-5339-5446)
- Julian Grandvallet Contreras (ORCID: https://orcid.org/0000-0001-8021-070X)
- Matthew T. Witkowski (ORCID: https://orcid.org/0000-0003-1434-4288)
- Angelo D’Alessandro (ORCID: https://orcid.org/0000-0002-2258-6490)
- Charles Grenfell Mullighan (ORCID: https://orcid.org/0000-0002-1871-1850)
- Markus Müschen (ORCID: https://orcid.org/0000-0002-6064-8613)
- Ilaria Iacobucci (ORCID: https://orcid.org/0000-0003-2008-1365)
- M. Eric Kohler (ORCID: https://orcid.org/0000-0002-1181-0418)
- Clarissa Garcia
- Colin C. Anderson (ORCID: https://orcid.org/0000-0001-7815-2416)
- John E. Dick (ORCID: https://orcid.org/0000-0002-9527-8317)
- Railey G. Mikeska
- Joshua Michlin
- Amy Argabright
- Xin Zhou (ORCID: https://orcid.org/0000-0003-3979-8200)
- Tian Liu (ORCID: https://orcid.org/0000-0002-1569-2084)
- Jesutomisin Olusoji
- Julie A. Reisz
- Abby Grier
- Sabrina Smith
- Kaylyn U. Lyons
- Tzu Phang
- Alexis J. Donnelly (ORCID: https://orcid.org/0009-0007-4078-3045)
- Hiten N. Patel (ORCID: https://orcid.org/0009-0004-3920-4809)
- Amanda J. Novak
Institutions
- St. Jude Children's Research Hospital (US)
- University of California, San Francisco (US)
- Princess Margaret Cancer Centre (CA)
- Yale Cancer Center (US)
- Children's Hospital Colorado (US)
- Center for Cancer and Blood Disorders (US)
- University of Colorado Anschutz Medical Campus (US)
- University of Colorado Denver (US)
Publication Details
- Journal
- Leukemia
- Published
- 2026-06-30
- DOI
- https://doi.org/10.1038/s41375-026-03030-0
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Society of Hematology
- Golfers Against Cancer
- Cancer League of Colorado
- Princess Margaret Cancer Foundation
- Ontario Institute for Cancer Research
- American Lebanese Syrian Associated Charities
- Morgan Adams Foundation
- Ontario Ministry of Health and Long-Term Care
- Canada Research Chairs
- Terry Fox Foundation
- Canadian Cancer Society Research Institute
- National Cancer Institute
- National Center for Advancing Translational Sciences
- CIHR Skin Research Training Centre