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ARTICLE - LIPA modulates venetoclax/TKI response in bpCML M. Minhajuddin et al.
enhance the post-transplant survival rates.
Finally, an important extension of our current work will be to expand our evaluation of combination therapies with venetoclax/TKI and fatty acid transport inhibitors or by extension autophagy inhibitors. Triple therapy combina- tions may enhance LSC targeting and extend durations of response given our preclinical data that blocking these pathways enhances efficacy of ven/dasa against bpCML. Understanding the mechanisms of synergy between vene- toclax and TKI in myeloid malignancies will be important to optimizing clinical use of this regimen.
In summary, we confirm and extend the preclinical utility of venetoclax/TKI combination therapies for targeting bpCML LSC. Furthermore, our data suggest that blocking upregu- lation of free fatty acids through mechanisms such as inhi- bition of LIPA activity might synergize with venetoclax/TKI combinations to eradicate LSC, allowing for more durable responses. Our findings support a therapeutic rationale for blocking pathways involved in free fatty acid generation as a potential strategy for increasing disease-free survival in patients affected by bpCML.
Disclosures
DAP has received research funding from and served as a consultant to AbbVie. The other authors declare no conflicts of interest.
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Contributions
MM and CTJ designed research. AW, HY, SP, BS, MA, AI, MG, MJA, RM, IS, SP, and AK performed and/or analyzed experi- ments. RC-H and AD’A performed the metabolomic analysis. AG, KE, SG, and MR performed the RNA sequencing analysis. MM prepared the figures. MM and CTJ wrote the manuscript with input from AW, SP, DWS, DAP, and CS.
Acknowledgments
The authors would like to acknowledge the patients who contributed to this research and the outstanding team at the Blood Disorders Center at the University of Colorado.
Funding
CTJ is supported by the Nancy Carroll Allen Chair in He- matology Research, a Leukemia and Lymphoma Society SCOR grant (7020-19), National Institutes of Health (NIH) R35CA242376, and Veterans Administration merit award BX004768-01. DAP is supported by the Robert H. Allen MD Chair in Hematology and the Leukemia and Lymphoma Society Scholar in Clinical Research. AW is supported by 1K08CA279762-01 through the NIH.
Data-sharing statement
Original data, primer/probe sequences, and protocols are available upon request by contacting the corresponding author.
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