CXCR4 allows T cell acute lymphoblastic leukemia to escape from JAK1/2 and BCL2 inhibition through CNS infiltration

Abstract

Targeting the JAK/STAT and BCL2 pathways in patients with relapsed/refractory T cell acute lymphoblastic leukemia (T-ALL) may provide an alternative approach to achieve clinical remissions. Ruxolitinib and venetoclax show a dose-dependent effect on T-ALL individually, but combination treatment reduces survival and proliferation of T-ALL in vitro. Using a xenograft model, the combination treatment fails to improve survival, with death from hind limb paralysis. Despite on-target inhibition by the drugs, histopathology demonstrates increased leukemic infiltration into the central nervous system (CNS) as compared to liver or bone marrow. Liquid chromatography-tandem mass spectroscopy shows that ruxolitinib and venetoclax insufficiently cross into the CNS. The addition of the CXCR4 inhibitor plerixafor with ruxolitinib and venetoclax reduces clinical scores and enhances survival. While combination therapy with ruxolitinib and venetoclax shows promise for treating T-ALL, additional inhibition of the CXCR4-CXCL12 axis may be needed to maximize the possibility of complete remission.

Keywords:

• T cell
• acute lymphoblastic leukemia
• ruxolitniib
• venetoclax
• plerixafor
• JAK/STAT
• BCL2

Acknowledgements

The authors thank Dennis Ea for his support on the project. The authors thank Nicole Piscopo and Krishanu Saha for providing the Jurkat-GFP cell line. The authors also thank the UWCCC Flow Cytometry core facility and UWCCC Experimental Pathology core facility, who are supported in part through NCI/NIH P30 CA014520 as well as the UW Biotechnology Center Genome Editing and Animal Model core facility and the Mass Spectrometry core facility, who is supported in part through NIGMS/NIH P50 GM64598 and NIDDK/NIH R33 DK070297 and the National Science Foundation (DBI-0520825, DBI-9977525). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation or the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. None of these funding sources had any input in the study design, analysis, manuscript preparation or decision to submit for publication.

Author contributions

KLW and CMC designed the experiments, analyzed and interpreted results and wrote the manuscript; NJH, SPR, SAK, FZ, SLO, MMC, AEQ, ASF, and TBG conducted experiments and analyzed data; NJH, SAK and SLO analyzed data and generated figures; and SPR, DPT, MNB and LR discussed and interpreted results. All authors read and approved the manuscript.

Disclosure statement

C.M.C reports honorarium from Nektar Therapeutics. This company had no input in the study design, analysis, manuscript preparation or decision to submit for publication. No other relevant conflicts of interest are reported.

Additional information

Funding

This work was supported by grants from the NHLBI/NIH T32 HL07899 (KLW), NIH TL1 TR002375 (SPR), Cormac Pediatric Leukemia Postdoctoral Fellowship (NJH), American Association for Immunologists Careers in Immunology Fellowship (MNB), NCI/NIH T32 CA009135 (MMC), NSF 1810916 WiscAMP Bridge to the Doctorate and NSF Graduate Research Fellowship Program DGE-1747503 (AEQ), American Society of Hematology HONORS award (TBG), NCI/NIH R01 CA187299 (LR), Alex’s Lemonade Stand Foundation POST program, St. Baldrick’s-Stand Up To Cancer Pediatric Dream Team Translational Research Grant SU2C-AACR-DT-27-17, Vince Lombardi Cancer Foundation, NCI/NIH K08 CA174750, NCI/NIH R01 CA215461 and the MACC Fund (CMC).