Lysosomal acid lipase A modulates leukemia stem cell response to venetoclax/tyrosine kinase inhibitor combination therapy in blast phase chronic myeloid leukemia

• Published in: Haematologica (Roma) Vol. 999; no. 1
• Main Authors: Minhajuddin, Mohd, Winters, Amanda, Ye, Haobin, Pei, Shanshan, Stevens, Brett, Gillen, Austin, Engel, Krysta, Gipson, Stephanie, Ransom, Monica, Amaya, Maria, Inguva, Anagha, Gasparetto, Maura, Althoff, Mark J, Miller, Regan, Shelton, Ian, Tolison, Hunter, Krug, Anna, Culp-Hill, Rachel, D'Alessandro, Angelo, Sherbenou, Daniel W, Pollyea, Daniel A, Smith, Clayton, Jordan, Craig T
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 27-06-2024
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2023.284716

The treatment of blast phase chronic myeloid leukemia (bpCML) remains a challenge due at least in part to drug resistance of leukemia stem cells (LSCs). Recent clinical evidence suggests that the BCL-2 inhibitor venetoclax in combination with ABL-targeting tyrosine kinase inhibitors (TKIs) can eradicate bpCML LSCs. In this report, we employed preclinical models of bpCML to investigate the efficacy and underlying mechanism of LSC-targeting with venetoclax/TKI combinations. Transcriptional analysis of LSCs exposed to venetoclax and dasatinib revealed upregulation of genes involved in lysosomal biology, in particular lysosomal acid lipase A (LIPA), a regulator of free fatty acids. Metabolomic analysis confirmed increased levels of free fatty acids in response to venetoclax/dasatinib. Pre-treatment of leukemia cells with bafilomycin, a specific lysosome inhibitor, or genetic perturbation of LIPA, resulted in increased sensitivity of leukemia cells toward venetoclax/dasatinib, implicating LIPA in treatment resistance. Importantly, venetoclax/dasatinib treatment does not affect normal stem cell function, suggestive of a leukemia-specific response. These results demonstrate that venetoclax/dasatinib is an LSCselective regimen in bpCML and that disrupting LIPA and fatty acid transport enhances venetoclax/dasatinib response in targeting LSCs, providing a rationale for exploring lysosomal disruption as an adjunct therapeutic strategy to prolong disease remission.