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from birth in the Tie2/FF1 mice, our murine model may not present the same acquired clonality and heteroge- neous vascular niche features that characterize patients with MPNs. Nonetheless, our study has demonstrated that the JAK2V617F-bearing vascular niche can protect the JAK2V617F HSPCs from the otherwise lethal irradiation administered during conditioning for marrow transplanta- tion, which provides a mechanism for the high incidence of disease relapse in MPN patients after allogeneic SCT. The optimal conditioning regimen for MPN patients undergoing SCT has still not been determined.44,48 As most current conditioning regimens for SCT are not restricted to only radiation, further investigation using murine mod- els with different quantities of mutant ECs versus WT ECs will be required to fully understand the effects of the JAK2V617F-bearing vascular niche on mutant HSPC
expansion and HSPC resistance to lethal irradiation and the cytotoxic chemotherapies commonly used in SCT for patients with MPNs.
Acknowledgments
The authors thank Todd Rueb and Rebecca Connor (Flow Cytometry Core Facility, Stony Brook University, NY, USA) for their assistance with the flow cytometry experiments. We would also like to thank Dr. Yupo Ma (Stony Brook University, NY, USA) for his continuous support throughout this work. YZ is supported by the State Scholarship Fund from Chinese Scholarship Council.
Funding
This research was supported by the Veterans Affairs award IK2BX001559 (HZ) and National Heart, Lung, and Blood Institute grant R01 HL134970 (HZ).
References
1. Walkley CR, Olsen GH, Dworkin S, et al. A microenvironment-induced myeloprolifer- ative syndrome caused by retinoic acid receptor gamma deficiency. Cell. 2007; 129(6):1097-1110.
2. Schepers K, Pietras EM, Reynaud D, et al. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self- reinforcing leukemic niche. Cell Stem Cell. 2013;13(3):285-299.
3. Arranz L, Sanchez-Aguilera A, Martin- Perez D, et al. Neuropathy of haematopoi- etic stem cell niche is essential for myelo- proliferative neoplasms. Nature. 2014; 512(7512):78-81.
4. Mager LF, Riether C, Schurch CM, et al. IL- 33 signaling contributes to the pathogene- sis of myeloproliferative neoplasms. J Clin Invest. 2015;125(7):2579-2591.
5. Walkley CR, Shea JM, Sims NA, Purton LE, Orkin SH. Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell. 2007;129(6):1081-1095.
6. Kroger N, Holler E, Kobbe G, et al. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multi- center study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2009;114(26):5264-5270.
7. Rondelli D, Goldberg JD, Isola L, et al. MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. Blood. 2014;124(7):1183- 1191.
8. Patriarca F, Bacigalupo A, Sperotto A, et al. Allogeneic hematopoietic stem cell trans- plantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Haematologica. 2008;93(10):1514-1522.
9. Morrison SJ, Scadden DT. The bone mar- row niche for haematopoietic stem cells. Nature. 2014;505(7483):327-334.
10. Medinger M, Skoda R, Gratwohl A, et al. Angiogenesis and vascular endothelial growth factor-/receptor expression in
myeloproliferative neoplasms: correlation with clinical parameters and JAK2-V617F mutational status. Br J Haematol. 2009;146(2):150-157.
11. Boveri E, Passamonti F, Rumi E, et al. Bone marrow microvessel density in chronic myeloproliferative disorders: a study of 115 patients with clinicopathological and molecular correlations. Br J Haematol. 2008;140(2):162-168.
12. Gianelli U, Vener C, Raviele PR, et al. VEGF expression correlates with microvessel den- sity in Philadelphia chromosome-negative chronic myeloproliferative disorders. Am J Clin Pathol. 2007;128(6):966-973.
13. Yoder MC, Mead LE, Prater D, et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood. 2007;109(5):1801-1809.
14. Teofili L, Martini M, Iachininoto MG, et al. Endothelial progenitor cells are clonal and exhibit the JAK2(V617F) mutation in a sub- set of thrombotic patients with Ph-negative myeloproliferative neoplasms. Blood. 2011;117(9):2700-2707.
15. Rosti V, Villani L, Riboni R, et al. Spleen endothelial cells from patients with myelofibrosis harbor the JAK2V617F muta- tion. Blood. 2013;121(2):360-368.
16. Sozer S, Ishii T, Fiel MI, et al. Human CD34+ cells are capable of generating nor- mal and JAK2V617F positive endothelial like cells in vivo. Blood Cells Mol Dis. 2009;43(3):304-312.
17. Piaggio G, Rosti V, Corselli M, et al. Endothelial colony-forming cells from patients with chronic myeloproliferative disorders lack the disease-specific molecu- lar clonality marker. Blood. 2009;114(14):3127-3130.
18. Sozer S, Fiel MI, Schiano T, Xu M, Mascarenhas J, Hoffman R. The presence of JAK2V617F mutation in the liver endothelial cells of patients with Budd- Chiari syndrome. Blood. 2009; 113(21):5246-5249.
19. Etheridge SL, Roh ME, Cosgrove ME, et al. JAK2V617F-positive endothelial cells con- tribute to clotting abnormalities in myelo- proliferative neoplasms. Proc Natl Acad Sci USA. 2014;111(6):2295-2300.
20. Zhan H, Lin CHS, Segal Y, Kaushansky K.
The JAK2V617F-bearing vascular niche promotes clonal expansion in myeloprolif- erative neoplasms. Leukemia. 2018; 32(2):462-469.
21. Lin CH, Kaushansky K, Zhan H. JAK2V617F-mutant vascular niche con- tributes to JAK2V617F clonal expansion in myeloproliferative neoplasms. Blood Cells Mol Dis. 2016;62:42-48.
22. Tiedt R, Hao-Shen H, Sobas MA, et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood. 2008;111(8):3931- 3940.
23. Constien R, Forde A, Liliensiek B, et al. Characterization of a novel EGFP reporter mouse to monitor Cre recombination as demonstrated by a Tie2 Cre mouse line. Genesis. 2001;30(1):36-44.
24. Duran-Struuck R, Dysko RC. Principles of bone marrow transplantation (BMT): pro- viding optimal veterinary and husbandry care to irradiated mice in BMT studies. J Am Assoc Lab Anim Sci. 2009;48(1):11-22.
25. Grahn D, Hamilton KF. Genetic Variation in the Acute Lethal Response of Four Inbred Mouse Strains to Whole Body X- Irradiation. Genetics. 1957;42(3):189-198.
26. Sangkhae V, Etheridge SL, Kaushansky K, Hitchcock IS. The thrombopoietin recep- tor, MPL, is critical for development of a JAK2V617F-induced myeloproliferative neoplasm. Blood. 2014;124(26):3956-3963.
27. Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005;121 (7):1109-1121.
28. Kent DG, Copley MR, Benz C, et al. Prospective isolation and molecular charac- terization of hematopoietic stem cells with durable self-renewal potential. Blood. 2009;113(25):6342-6350.
29. Hooper AT, Butler JM, Nolan DJ, et al. Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2- mediated regeneration of sinusoidal endothelial cells. Cell Stem Cell. 2009;4(3):263-274.
30. Doan PL, Russell JL, Himburg HA, et al. Tie2(+) bone marrow endothelial cells reg- ulate hematopoietic stem cell regeneration
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