Therapy-Resistant Acute Myeloid Leukemia Stem Cells Are Resensitized to Venetoclax

Recent advances in targeting leukemic stem cells (LSCs) using venetoclax with azacitidine (ven + aza) has significantly improved outcomes for de novo acute myeloid leukemia (AML) patients. However, patients who relapse after traditional chemotherapy are often venetoclax-resistant and exhibit poor clinical outcomes. We previously described that fatty acid metabolism drives oxidative phosphorylation (OXPHOS) and acts as a mechanism of LSC survival in relapsed/refractory AML. Here, we report that chemotherapy-relapsed primary AML displays aberrant fatty acid and lipid metabolism, as well as increased fatty acid desaturation through the activity of fatty acid desaturases 1 and 2, and that fatty acid desaturases function as a mechanism of recycling NAD+ to drive relapsed LSC survival. When combined with ven + aza, the genetic and pharmacologic inhibition of fatty acid desaturation results in decreased primary AML viability in relapsed AML. This study includes the largest lipidomic profile of LSC-enriched primary AML patient cells to date and indicates that inhibition of fatty acid desaturation is a promising therapeutic target for relapsed AML.

Automated summary

Recent advances in targeting leukemic stem cells (LSCs) with venetoclax and azacitidine (ven + aza) have improved outcomes for de novo acute myeloid leukemia (AML) patients. However, relapsed AML patients often develop resistance to venetoclax and have poor clinical outcomes. This study shows that fatty acid desaturation drives relapsed AML survival and inhibiting it could be a promising therapeutic target for relapsed AML, as demonstrated by decreased AML viability when combining fatty acid desaturation inhibition with ven + aza.