LPCAT3 is essential for leukemia progression and represents a therapeutic vulnerability in AML.

Acute myeloid leukemia (AML) is a group of genetically and clinically heterogeneous malignancies characterized by clonal expansion of immature myeloid progenitors and profound disruption of normal hematopoiesis. Emerging evidence suggests that alterations in cellular homeostasis shape cancer progression. However, the mechanisms underlying AML progression remain largely unclear. Here, we identify lysophosphatidylcholine acyltransferase 3 (LPCAT3), a key enzyme of the Lands' cycle, as a critical regulator of AML progression. Analysis of public transcriptomic datasets and patient-derived CD34+ cells revealed robust LPCAT3 overexpression in AML and an association between high LPCAT3 levels and inferior overall AML patient survival. Suppression of LPCAT3 by shRNA or CRISPR-Cas9 in MOLM-13 and THP-1 cells markedly impaired proliferation, induced apoptosis, and caused G0/G1 cell-cycle arrest. Conversely, enforced overexpression promoted cell survival. In xenograft murine models, LPCAT3 depletion reduced leukemic burden. RNA-seq following LPCAT3 loss showed that genes differentially expressed were significantly enriched in granulocyte chemotaxis-related pathways, suggesting a role of LPCAT3 in modulation of leukemic differentiation programs and microenvironmental interactions. Collectively, these data established that LPCAT3 as a previously unrecognized mediator of AML cell fitness and as a potential therapeutic target.