Page 84 - 2021_06-Haematologica-web

J.C. Gutjahr et al.
xenograft model we could not establish a treatment regime of combined VLA-4 inhibition and induction chemotherapy with a survival benefit for the mice. While this argues for kinase inhibition as the preferential cytarabine combination partner, it does not exclude a role of VLA-4 inhibition in other treatment schedules or at other disease points, e.g. during graft-versus-host management.
Taking all our data together, we suggest that HA binding to CD44 triggers a signaling axis via SFK and PI3K to rapidly trigger VLA-4 avidity and hence support the retention of AML cells in their preferential niches (Figure 7). Compensatory survival mechanisms of malignant cells still comprise a major challenge in current AML therapy which may be tackled by the use of combinatorial therapies, administering kinase inhibitors that may help to interfere with cellular position as well as growth signaling accompa- nied by drugs inducing apoptosis, as a step forward in improving current treatment modalities.
Disclosures
No conflicts of interest to disclose.
Contributions
JCG and TNH conceived and designed the study and wrote the manuscript. JCG, EB, XY, JML, AR, AC and DN devel- oped the methodology. JCG, EB, XY, JML, JPH, GA, TR, AS, ES, TH, AH, ST, SP, AR, MA, AC and DN acquired data. JCG, EB, XY, JML, GA, TR, AS, AH, AC, DN, DFL; VO-R,
RG and TNH analyzed and interpreted the data. JCG, EB, XY, JML,, JPH, GA, ST, TR, AS, ES, VD-O, AR, AH, NZ, AC, FA, DN and DFL reviewed and/or revised the manu- script. RG, LP, DN, DFL, VO-R. FA and TNH provided administrative, technical, or material support. TNH supervised the study.
Acknowledgments
We thank all patients for their participation in this study. We also thank the staff from Charles River Research Services Germany GmbH for excellent technical support. We thank Christoph Ratswohl for helpful revision of the manuscript and Alexandra Hödlmoser for support with handling the mice.
Funding
This work was supported by the SCRI-LIMCR GmbH, the province of Salzburg as support to the Cancer Cluster Salzburg work package 2, the Austrian Science Fund (FWF) 25015-B13 (to TNH), the PhD program Immunity in Cancer and Allergy (W1213, Austrian Science Fund) (to TNH, FA and RG), the Paracelsus Medical University PMU-FFF E-15/22/114-HAR (to TNH), the Wilhelm-Seiter Stiftung Freiburg (to TNH), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – 419090910 (to TNH) and the Swiss National Science Foundation (169936 & 189144) (to DFL). This work was also supported by the National Institutes of Health (USA) grant: UNM Comprehensive Cancer Center CCSG P30 CA118100 (to AC).
References
1. Zhou HS, Carter BZ, Andreeff M. Bone mar- row niche-mediated survival of leukemia stem cells in acute myeloid leukemia: yin and yang. Cancer Biol Med. 2016;13(2):248- 259.
2. Naor D, Nedvetzki S, Golan I, Melnik L, Faitelson Y. CD44 in cancer. Crit Rev Clin Lab Sci. 2002;39(6):527-579.
3. Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 2006;12(10):1167-1174.
4. Alon R, Dustin ML. Force as a facilitator of integrin conformational changes during leukocyte arrest on blood vessels and anti- gen-presenting cells. Immunity. 2007;26(1): 17-27.
5. Dustin ML, Bivona TG, Philips MR. Membranes as messengers in T cell adhe- sion signaling. Nat Immunol. 2004;5(4):363- 372.
6. Lundell BI, McCarthy JB, Kovach NL, Verfaillie CM. Activation of beta1 integrins on CML progenitors reveals cooperation between beta1 integrins and CD44 in the regulation of adhesion and proliferation. Leukemia. 1997;11(6):822-829.
7. Verfaillie CM, Benis A, Iida J, McGlave PB, McCarthy JB. Adhesion of committed human hematopoietic progenitors to syn- thetic peptides from the C-terminal heparin- binding domain of fibronectin: cooperation between the integrin alpha 4 beta 1 and the CD44 adhesion receptor. Blood. 1994;84(6): 1802-1811.
8. Singh V, Erb U, Zoller M. Cooperativity of CD44 and CD49d in leukemia cell homing, migration, and survival offers a means for therapeutic attack. J Immunol. 2013;191(10): 5304-5316.
9.Brachtl G, Sahakyan K, Denk U et al.
Differential bone marrow homing capacity of VLA-4 and CD38 high expressing chronic lymphocytic leukemia cells. PLoS One. 2011;6(8):e23758.
10. Gutjahr JC, Szenes E, Tschech L, et al. Microenvironment-induced CD44v6 pro- motes early disease progression in chronic lymphocytic leukemia. Blood. 2018;131(12): 1337-1349.
11. Tissino E, Benedetti D, Herman SEM, et al. Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia. J Exp Med. 2018;215(2): 681-697
12. Laufer JM, Lyck R, Legler DF. ZAP70 expres- sion enhances chemokine-driven chronic lymphocytic leukemia cell migration and arrest by valency regulation of integrins. FASEB J. 2018;32(9):4824-4835.
13. Lacombe F, Durrieu F, Briais A, et al. Flow cytometry CD45 gating for immunopheno- typing of acute myeloid leukemia. Leukemia. 1997;11(11):1878-1886.
14. Lapidot T, Dar A, Kollet O. How do stem cells find their way home? Blood. 2005;106 (6):1901-1910.
15. Ganghammer S, Hutterer E, Hinterseer E, et al. CXCL12-induced VLA-4 activation is impaired in trisomy 12 chronic lymphocytic leukemia cells: a role for CCL21. Oncotarget. 2015;6(14):12048-12060.
16. Tavianatou AG, Caon I, Franchi M, Piperigkou Z, Galesso D, Karamanos NK. Hyaluronan: molecular size-dependent sig- naling and biological functions in inflamma- tion and cancer. FEBS J. 2019;286(15):2883- 2908.
17. Peled A, Kollet O, Ponomaryov T, et al. The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34(+) cells: role in transendothe- lial/stromal migration and engraftment of
NOD/SCID mice. Blood. 2000;95(11):3289-
3296.
18. Chigaev A, Zwartz GJ, Buranda T, Edwards
BS, Prossnitz ER, Sklar LA. Conformational regulation of alpha 4 beta 1-integrin affinity by reducing agents. "Inside-out" signaling is independent of and additive to reduction- regulated integrin activation. J Biol Chem. 2004;279(31):32435-32443.
19.Kim M, Carman CV, Yang W, Salas A, Springer TA. The primacy of affinity over clustering in regulation of adhesiveness of the integrin {alpha}L{beta}2. J Cell Biol. 2004;167(6):1241-1253.
20.Chigaev A, Waller A, Amit O, Halip L, Bologa CG, Sklar LA. Real-time analysis of conformation-sensitive antibody binding provides new insights into integrin confor- mational regulation. J Biol Chem. 2009;284 (21):14337-14346.
21. Alon R, Feigelson SW, Manevich E, et al. Alpha4beta1-dependent adhesion strength- ening under mechanical strain is regulated by paxillin association with the alpha4-cyto- plasmic domain. J Cell Biol. 2005;171(6): 1073-1084.
22. Legras S, Gunthert U, Stauder R, et al. A strong expression of CD44-6v correlates with shorter survival of patients with acute myeloid leukemia. Blood. 1998;91(9):3401- 3413.
23.Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regula- tors. Nat Rev Mol Cell Biol. 2003;4(1):33-45.
24. Bouaouina M, Blouin E, Halbwachs- Mecarelli L, Lesavre P, Rieu P. TNF-induced beta2 integrin activation involves Src kinases and a redox-regulated activation of p38 MAPK. J Immunol. 2004;173(2):1313-1320.
25. Gadhoum SZ, Madhoun NY, Abuelela AF, Merzaban JS. Anti-CD44 antibodies inhibit both mTORC1 and mTORC2: a new
2112
haematologica | 2021; 106(8)