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Attenuating leukemia chemoresistance in the CNS
tifaceted mechanism of action of Me6TREN may provide an advantage relative to other niche-disrupting agents being developed for leukemia therapy that target a single mechanism of retention or adhesion (i.e. inhibitors of SDF-1 or a single extracellular adhesion factor).57 An alter- native approach to overcome the complexity and redun- dancy of cellular adhesion would be to combine multiple inhibitors that target different adhesion molecules (Online Supplementary Figure S6A).
A potential risk of combining Me6TREN, or other niche-disrupting agents, and chemotherapy is that nor- mal hematopoietic stem cells mobilized into the circula- tion by Me6TREN may be sensitized to chemotherapy with resulting marrow aplasia or delayed hematopoietic recovery. However, we found that mice receiving cytara- bine/Me6TREN or cytarabine alone exhibited compara- ble hematologic toxicities. Moreover, preclinical and clin- ical studies combining other hematopoietic stem cell- mobilizing agents, such as AMD3100 or granulocyte colony-stimulating factor, with chemotherapy have also shown an acceptable toxicity profile.58,59 Another poten- tial limitation to this approach of disrupting leukemia cell adhesion to the niche is that soluble factors secreted by the niche can also interact with non-adherent leukemia cells and affect leukemia biology, as we saw with meningeal conditioned media.46,60 Combination therapies that target both adhesion and secreted factors
may be the most efficacious in treatment of CNS leukemia.
In summary, this work demonstrates that the meninges enhance leukemia chemoresistance in the CNS, elucidates mechanisms of CNS relapse beyond the role of the blood- brain barrier, and identifies niche disruption as a novel therapeutic approach for enhancing the ability of chemotherapy to eradicate CNS leukemia.
Acknowledgments
This work was supported in part by the Children’s Cancer Research Fund (PMG), the Timothy O’Connell Foundation (PMG), and an American Cancer Society Institutional Research Grant (PMG). PB was partially supported by NIH Training Grant T32 CA099936. We thank Dr. Michael Farrar for provid- ing mouse BCR/ABL p190 leukemia cells, Dr. Juan Abrahante Lloréns (University of Minnesota Genomics Center) for assistance with RNA-sequencing data analyses, Dr. Mark Sanders (University of Minnesota Imaging Center) for providing expert assistance with confocal microscopy and sample preparation, and Mike Ehrhardt (University of Minnesota Cytokine Reference Laboratory) for assistance with measuring cytokine levels. This work utilized the University of Minnesota Masonic Cancer Center shared flow cytometry and comparative pathology resources and the Hematological Malignancy Tissue Bank, which are supported in part by NCI 5P30CA077598-18, Minnesota Masonic Charities, and the Killebrew-Thompson Memorial Fund.
References
1. Pui C-H, Howard SC. Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol. 2008;9(3):257-268.
2. Pui C-H, Thiel E. Central nervous system disease in hematologic malignancies: histor- ical perspective and practical applications. Semin Oncol. 2009;36(4 Suppl 2):S2-16.
3. Pui C-H. Central nervous system disease in acute lymphoblastic leukemia: prophylaxis and treatment. Hematology Am Soc Hematol Educ Program. 2006;142-146.
4. Silverman LB. Balancing cure and long-term risks in acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2014;2014(1):190-197.
5. Hijiya N, Hudson MM, Lensing S, et al. Cumulative incidence of secondary neo- plasms as a first event after childhood acute lymphoblastic leukemia. JAMA. 2007; 297(11):1207-1215.
6. Conklin HM, Krull KR, Reddick WE, Pei D, Cheng C, Pui CH. Cognitive outcomes fol- lowing contemporary treatment without cranial irradiation for childhood acute lym- phoblastic leukemia. J Natl Cancer Inst. 2012;104(18):1386-1395.
7. Krull KR, Brinkman TM, Li C, et al. Neurocognitive outcomes decades after treatment for childhood acute lymphoblas- tic leukemia: a report from the St Jude life- time cohort study. J Clin Oncol. 2013;31(35):4407-4415.
8. Bhojwani D, Sabin ND, Pei D, et al. Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol. 2014;32(9):949-959.
9. Iyer NS, Balsamo LM, Bracken MB, Kadan- Lottick NS. Chemotherapy-only treatment effects on long-term neurocognitive func- tioning in childhood ALL survivors: a review and meta-analysis. Blood. 2015;126(3):346- 353.
10. Pui C-H, Cheng C, Leung W, et al. Extended follow-up of long-term survivors of child- hood acute lymphoblastic leukemia. N Engl J Med. 2003;349(7):640-649.
11. Price RA. Histopathology of CNS leukemia and complications of therapy. Am J Pediatr Hematol Oncol. 1979;1(1):21-30.
12. Price RA, Johnson WW. The central nervous system in childhood leukemia. I. The arach- noid. Cancer. 1973;31(3):520-533.
13. Evans AE, Gilbert ES, Zandstra R. The increasing incidence of central nervous sys- tem leukemia in children. (Children’s Cancer Study Group A). Cancer. 1970;26(2):404- 409.
14. Williams MTS, Yousafzai YM, Elder A, et al. The ability to cross the blood-cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukemia blasts. Blood. 2016;127(16):1998-2006.
15. Bartram J, Goulden N, Wright G, et al. High throughput sequencing in acute lym- phoblastic leukemia reveals clonal architec- ture of central nervous system and bone marrow compartments. Haematologica. 2018;103(3):e110-114.
16. Krause S, Pfeiffer C, Strube S, et al. Mer tyro- sine kinase promotes the survival of t(1;19)- positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS). Blood. 2015;125(5):820-830.
17. Akers SM, Rellick SL, Fortney JE, Gibson LF. Cellular elements of the subarachnoid space promote ALL survival during chemotherapy. Leuk Res. 2011;35(6):705-711.
18. Gossai NP, Gordon PM. The role of the cen- tral nervous system microenvironment in pediatric acute lymphoblastic leukemia. Front Pediatr. 2017;5:90.
19. Frishman-Levy L, Izraeli S. Advances in understanding the pathogenesis of CNS acute lymphoblastic leukaemia and poten- tial for therapy. Br J Haematol. 2017;176 (2):157-167.
20. Gaynes JS, Jonart LM, Zamora EA, Naumann JA, Gossai NP, Gordon PM. The central nervous system microenvironment influences the leukemia transcriptome and enhances leukemia chemo-resistance. Haematologica. 2017;102(4):e136-139.
21. Williams RT, Sherr CJ. The ARF tumor sup- pressor in acute leukemias: insights from mouse models of Bcr-Abl-induced acute lymphoblastic leukemia. Adv Exp Med Biol. 2007;604:107-114.
22. Mishra S, Zhang B, Cunnick JM, Heisterkamp N, Groffen J. Resistance to imatinib of bcr/abl p190 lymphoblastic leukemia cells. Cancer Res. 2006;66 (10):5387-5393.
23. Williams RT, Roussel MF, Sherr CJ. Arf gene loss enhances oncogenicity and limits ima- tinib response in mouse models of Bcr-Abl- induced acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 2006;103(17):6688-6693.
24. Townsend EC, Murakami MA, Christodoulou A, et al. The public reposito- ry of xenografts enables discovery and ran- domized phase II-like yrials in mice. Cancer Cell. 2016;29(4):574-586.
25. Liu L, Duff K. A technique for serial collec- tion of cerebrospinal fluid from the cisterna magna in mouse. J Vis Exp. 2008;(21).
26. Manlove LS, Schenkel JM, Manlove KR, et al. Heterologous vaccination and checkpoint blockade synergize to induce antileukemia
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