Page 21 - Haematologica Vol. 110 - January 2025

EDITORIAL
LIPA-frogging blast phase chronic myeloid leukemia: hopping over resistance with lysosomal targeting
Miguel Quijada-Álamo, Grace Freed and Elvin Wagenblast
Department of Oncological Sciences, Tisch Cancer Institute, Black Family Stem Cell Institute, Mindich Child Health & Development Institute and Department of Pediatrics, Division of Pediatric Hematology-Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
In this issue of Haematologica, Minhajuddin et al.1 pro- vide a compelling analysis of the combinatorial therapy of venetoclax and tyrosine kinase inhibitors (TKI) for treating blast phase chronic myeloid leukemia (bpCML). Despite significant improvements in the outcomes of patients with chronic myeloid leukemia (CML) due to the development of TKI, a subset of patients still progresses to bpCML, which is associated with dismal prognosis and a median survival of less than 1 year.2 The treatment of bpCML remains a sig- nificant challenge due to drug resistance of leukemia stem cells (LSC),3 requiring the development of new therapeutic strategies that specifically target this resistant population. Preclinical studies have indicated that combining the selec- tive BCL-2 inhibitor venetoclax with TKI holds promise for both chronic phase and bpCML.4 Minhajuddin et al. delve into the mechanistic underpinnings of this combinatorial therapy, identifying a key role for lysosomal acid lipase A (LIPA) in the adaptative response of bpCML LSC and high- lighting a new vulnerability of these cells to the disruption of lysosomal function.1
BCL-2 family members are proteins involved in mito- chondrial-related apoptosis and have been shown to be critical for the survival of leukemia cells. Indeed, selective inhibition of the anti-apoptotic protein BCL-2 by the Food and Drug Administration-approved compound venetoclax has emerged as a promising strategy for the treatment of various lymphoid and myeloid leukemias.5 In CML, BCL-2 levels are higher than in normal hematopoietic stem cells and are further increased in bpCML.6 Since TKI treat- ment alone often fails to eradicate CML LSC, combining venetoclax with TKI could enhance treatment efficacy, particularly in bpCML. Minhajuddin et al. demonstrate that the combination of venetoclax and dasatinib does indeed effectively target LSC in both the Bcr-Abl Nup98- Hoxa9 bpCML mouse model and in primary bpCML cells. This combination therapy led to complete elimination of bpCML cells and, importantly, LSC exposed to the drug
combination were not able to engraft in secondary re- cipients, indicating successful eradication of the bpCML LSC compartment. Furthermore, they generated a novel bpCML mouse model harboring the T315I Bcr-Abl muta- tion in combination with Nup98-Hoxa9 translocation and showed enhanced efficacy of venetoclax in combination with the third-generation TKI ponatinib. This is of particular relevance since more than 40% of bpCML cases harbor tyrosine-kinase domain mutations in BCR-ABL, confer- ring resistance to earlier-generation TKI.7 It would be of special interest in future studies to assess the efficacy of venetoclax in combination with the next-generation TKI asciminib, which has been shown to be active in CML patients after the failure of ponatinib or other TKI.8 Understanding the molecular mechanisms underlying the bpCML LSC-targeting activity of venetoclax and TKI combi- nation therapy is crucial for anticipating potential mecha- nisms of resistance and identifying new actionable pathways that could be leveraged to enhance therapeutic outcomes. Minhajuddin et al. performed RNA sequencing of bone mar- row LSC-sorted populations treated with dasatinib alone or combined with venetoclax, revealing an upregulation of genes involved in lysosomal biology in cells exposed to the combination therapy. Notably, LIPA, an enzyme involved in free fatty acid regulation, was significantly elevated in LSC treated with both venetoclax and dasatinib, result- ing in increased production of several fatty acids such as g-linolenic acid and dihomo-g-linolenic acid. LIPA overex- pression in murine bpCML LSC or fatty acid media supple- mentation conferred partial resistance to the combination therapy. Conversely, LIPA knockout in murine bpCML LSC, LIPA knockdown in primary bpCML cells and inhibition of lysosomal function with bafilomycin increased sensitivity to the treatment. Collectively, these results indicate that LIPA-driven lysosomal and fatty acid pathways contribute to the protective response of bpCML LSC to venetoclax and TKI, laying the ground for further exploration of these
Haematologica | 110 January 2025
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Correspondence: E. Wagenblast elvin.wagenblast@mssm.edu
Received: Accepted: Early view:
July 30, 2024. August 9, 2024. August 22, 2024.
https://doi.org/10.3324/haematol.2024.286140
©2025 Ferrata Storti Foundation Published under a CC BY-NC license