Page 111 - Haematologica Vol. 110 - January 2025

ARTICLE - Chronic Myeloid Leukemia
Lysosomal acid lipase A modulates leukemia stem cell response to venetoclax/tyrosine kinase inhibitor combination therapy in blast phase chronic myeloid leukemia
Mohd Minhajuddin,1 Amanda Winters,2 Haobin Ye,3 Shanshan Pei,4 Brett Stevens,1 Austin Gillen,1 Krysta Engel,1 Stephanie Gipson,1 Monica Ransom,1 Maria Amaya,1 Anagha Inguva,1 Maura Gasparetto,1 Mark J. Althoff,1 Regan Miller,1 Ian Shelton,1 Hunter Tolison,1 Anna Krug,1 Rachel Culp-Hill,5 Angelo D’Alessandro,5 Daniel W. Sherbenou,1 Daniel A. Pollyea,1 Clayton Smith1 and Craig T. Jordan1
1Division of Hematology, University of Colorado School of Medicine, Aurora, CO, USA; 2Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA; 3Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism & Integrative Biology, Fudan University, Shanghai, China; 4Liangzhu Laboratory, Zhejiang University Medical Center, Zhejiang, China and 5Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Abstract
The treatment of blast phase chronic myeloid leukemia (bpCML) remains a challenge due, at least in part, to drug resistance of leukemia stem cells (LSC). Recent clinical evidence suggests that the BCL-2 inhibitor venetoclax in combination with ABL-targeting tyrosine kinase inhibitors can eradicate bpCML LSC. In this study, we employed preclinical models of bpCML to investigate the efficacy and underlying mechanism of LSC-targeting with combinations of venetoclax/tyrosine kinase inhibitors. Transcriptional analysis of LSC 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 treatment with venetoclax/dasatinib. Pretreatment of leukemia cells with bafilomycin, a specific lysosome inhibitor, or genetic perturbation of LIPA, resulted in increased sensitivity of leukemia cells to venetoclax/dasatinib, implicating LIPA in treatment resistance. Importantly, venetoclax/dasatinib treatment did not affect normal stem cell function, suggesting a leukemia-specific response. These results demonstrate that venetoclax/dasatinib is a LSC-selective regimen in bpCML and that disrupting LIPA and fatty acid transport enhances the response to venetoclax/ dasatinib when targeting LSC, providing a rationale for exploring lysosomal disruption as an adjunctive therapeutic strategy to prolong disease remission.
Introduction
Chronic myeloid leukemia (CML) is caused by reciprocal translocation of chromosomes 9 and 22, resulting in the generation of a BCR-ABL fusion protein and constitutive acti- vation of the ABL tyrosine kinase.1 The existence of leukemia stem cells (LSC) in both chronic phase CML (cpCML) and blast phase CML (bpCML) is supported by previous studies.2,3 ABL tyrosine kinase inhibitors (TKI) are to date one of the most successful targeted therapies for malignant disease.4 Unfortunately, TKI do not always eliminate disease-initiating LSC, as evidenced by an inability to discontinue TKI therapy
in at least 50% of patients who achieve and maintain a deep molecular response for a significant period.5
CML is classified into three phases: chronic, accelerated and blast phase. bpCML, characterized by the acquisition of secondary mutations in addition to t(9;22) and transition to an often treatment-refractory acute leukemia, remains a formidable challenge in the management of CML.6 In bpCML, emergence of TKI resistance frequently occurs through de- velopment of tyrosine kinase domain mutations in BCR-ABL. These include the “gatekeeper” T315I mutation, which results from a threonine to isoleucine substitution at position 315 of ABL, leading to resistance to first- and second-generation
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Correspondence: M. Minhajuddin mohd.minhajuddin@cuanschutz.edu
Received: Accepted: Early view:
November 22, 2023. June 20, 2024. June 27, 2024.
https://doi.org/10.3324/haematol.2023.284716
©2025 Ferrata Storti Foundation Published under a CC BY-NC license