Therapy-Resistant Acute Myeloid Leukemia Stem Cells Are Resensitized to Venetoclax + Azacitidine by Targeting Fatty Acid Desaturases 1 and 2.
Rachel Culp-HillBrett M StevensCourtney L JonesShanshan PeiMonika DzieciatkowskaMohammad MinhajuddinCraig T JordanAngelo D'AlessandroPublished in: Metabolites (2023)
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.
Keyphrases
- acute myeloid leukemia
- fatty acid
- allogeneic hematopoietic stem cell transplantation
- stem cells
- induced apoptosis
- end stage renal disease
- adipose tissue
- type diabetes
- acute lymphoblastic leukemia
- squamous cell carcinoma
- cell proliferation
- drug delivery
- genome wide
- peritoneal dialysis
- case report
- free survival
- copy number