REFERENCES
1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391-405.
2. Acar M, Kocherlakota KS, Murphy MM, et al. Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature 2015;526:126-30.
3. Beerman I, Luis TC, Singbrant S, Lo Celso C, Méndez-Ferrer S. The evolving view of the hematopoietic stem cell niche. Exp Hematol 2017;50:22-6.
4. Kunisaki Y, Bruns I, Scheiermann C, et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 2013;502:637-43.
5. Kusumbe AP, Ramasamy SK, Adams RH. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 2014;507:323-8.
6. Falkowski M, Schledzewski K, Hansen B, Goerdt S. Expression of stabilin-2, a novel fasciclin-like hyaluronan receptor protein, in murine sinusoidal endothelia, avascular tissues, and at solid/liquid interfaces. Histochem Cell Biol 2003;120:361-9.
7. Baryawno N, Przybylski D, Kowalczyk MS, et al. A cellular taxonomy of the bone marrow stroma in homeostasis and leukemia. Cell 2019;177:1915-1932.e16.
8. Ding L, Saunders TL, Enikolopov G, Morrison SJ. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 2012;481:457-62.
9. Omatsu Y, Sugiyama T, Kohara H, et al. The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity 2010;33:387-99.
10. Mende N, Jolly A, Percin GI, et al. Prospective isolation of nonhematopoietic cells of the niche and their differential molecular interactions with HSCs. Blood 2019;134:1214-26.
11. Itkin T, Gur-Cohen S, Spencer JA, et al. Distinct bone marrow blood vessels differentially regulate haematopoiesis. Nature 2016;532:323-8.
12. García-García A, Korn C, García-Fernández M, et al. Dual cholinergic signals regulate daily migration of hematopoietic stem cells and leukocytes. Blood 2019;133:224-36.
13. Méndez-Ferrer S, Lucas D, Battista M, Frenette PS. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 2008;452:442-7.
14. Zhao M, Tao F, Venkatraman A, et al. N-cadherin-expressing bone and marrow stromal progenitor cells maintain reserve hematopoietic stem cells. Cell Rep 2019;26:652-669.e6.
15. Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 2006;25:977-88.
16. Taichman RS, Emerson SG. Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor. J Exp Med 1994;179:1677-82.
17. Zhang J, Niu C, Ye L, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 2003;425:836-41.
18. Calvi LM, Adams GB, Weibrecht KW, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 2003;425:841-6.
19. Arai F, Hirao A, Ohmura M, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 2004;118:149-61.
20. Yoshihara H, Arai F, Hosokawa K, et al. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell 2007;1:685-97.
21. Adams GB, Chabner KT, Alley IR, et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 2006;439:599-603.
22. Méndez-Ferrer S, Michurina TV, Ferraro F, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010;466:829-34.
23. Saçma M, Pospiech J, Bogeska R, et al. Haematopoietic stem cells in perisinusoidal niches are protected from ageing. Nat Cell Biol 2019;21:1309-20.
24. Pinho S, Marchand T, Yang E, Wei Q, Nerlov C, Frenette PS. Lineage-biased hematopoietic stem cells are regulated by distinct niches. Dev Cell 2018;44:634-41.e4.
25. Miller JP, Allman D. The decline in B lymphopoiesis in aged mice reflects loss of very early B-lineage precursors. J Immunol 2003;171:2326-30.
26. Min H, Montecino-Rodriguez E, Dorshkind K. Effects of aging on the common lymphoid progenitor to pro-B cell transition. J Immunol 2006;176:1007-12.
27. Baccin C, Al-Sabah J, Velten L, et al. Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nat Cell Biol 2020;22:38-48.
28. Yamazaki S, Ema H, Karlsson G, et al. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 2011;147:1146-58.
29. Bruns I, Lucas D, Pinho S, et al. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med 2014;20:1315-20.
30. Zhao M, Perry JM, Marshall H, et al. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat Med 2014;20:1321-6.
31. Nakamura-Ishizu A, Takubo K, Kobayashi H, Suzuki-Inoue K, Suda T. CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in the bone marrow. J Exp Med 2015;212:2133-46.
32. Kinashi T, Springer TA. Steel factor and c-kit regulate cell-matrix adhesion. Blood 1994;83:1033-8.
33. Post Y, Clevers H. Defining adult stem cell function at its simplest: the ability to replace lost cells through mitosis. Cell Stem Cell 2019;25:174-83.
34. Asada N, Kunisaki Y, Pierce H, et al. Differential cytokine contributions of perivascular haematopoietic stem cell niches. Nat Cell Biol 2017;19:214-23.
35. Comazzetto S, Murphy MM, Berto S, Jeffery E, Zhao Z, Morrison SJ. Restricted hematopoietic progenitors and erythropoiesis require SCF from leptin receptor+ niche cells in the bone marrow. Cell Stem Cell 2019;24:477-486.e6.
36. Dührsen U, Hossfeld DK. Stromal abnormalities in neoplastic bone marrow diseases. Ann Hematol 1996;73:53-70.
37. Bowman RL, Busque L, Levine RL. Clonal hematopoiesis and evolution to hematopoietic malignancies. Cell Stem Cell 2018;22:157-70.
39. Raaijmakers MH, Mukherjee S, Guo S, et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 2010;464:852-7.
40. Santamaría C, Muntión S, Rosón B, et al. Impaired expression of DICER, DROSHA, SBDS and some microRNAs in mesenchymal stromal cells from myelodysplastic syndrome patients. Haematologica 2012;97:1218-24.
41. Zambetti NA, Ping Z, Chen S, et al. Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia. Cell Stem Cell 2016;19:613-27.
43. Kode A, Manavalan JS, Mosialou I, et al. Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. Nature 2014;506:240-4.
44. Wang J, Fernald AA, Anastasi J, Le Beau MM, Qian Z. Haploinsufficiency of Apc leads to ineffective hematopoiesis. Blood 2010;115:3481-8.
45. Lane SW, Sykes SM, Al-Shahrour F, et al. The Apc(min) mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS. Blood 2010;115:3489-97.
46. Li L, Sheng Y, Li W, et al. β-Catenin is a candidate therapeutic target for myeloid neoplasms with del(5q). Cancer Res 2017;77:4116-26.
47. Rupec RA, Jundt F, Rebholz B, et al. Stroma-mediated dysregulation of myelopoiesis in mice lacking I kappa B alpha. Immunity 2005;22:479-91.
48. Walkley CR, Shea JM, Sims NA, Purton LE, Orkin SH. Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell 2007;129:1081-95.
49. Kim YW, Koo BK, Jeong HW, et al. Defective Notch activation in microenvironment leads to myeloproliferative disease. Blood 2008;112:4628-38.
50. Zimmer SN, Zhou Q, Zhou T, et al. Crebbp haploinsufficiency in mice alters the bone marrow microenvironment, leading to loss of stem cells and excessive myelopoiesis. Blood 2011;118:69-79.
51. Walkley CR, Olsen GH, Dworkin S, et al. A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency. Cell 2007;129:1097-110.
52. Dong L, Yu WM, Zheng H, et al. Leukaemogenic effects of Ptpn11 activating mutations in the stem cell microenvironment. Nature 2016;539:304-8.
53. Tartaglia M, Mehler EL, Goldberg R, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 2001;29:465-8.
54. Tartaglia M, Niemeyer CM, Fragale A, et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 2003;34:148-50.
55. Blau O, Baldus CD, Hofmann WK, et al. Mesenchymal stromal cells of myelodysplastic syndrome and acute myeloid leukemia patients have distinct genetic abnormalities compared with leukemic blasts. Blood 2011;118:5583-92.
56. Blau O, Hofmann WK, Baldus CD, et al. Chromosomal aberrations in bone marrow mesenchymal stroma cells from patients with myelodysplastic syndrome and acute myeloblastic leukemia. Exp Hematol 2007;35:221-9.
57. Huang JC, Basu SK, Zhao X, et al. Mesenchymal stromal cells derived from acute myeloid leukemia bone marrow exhibit aberrant cytogenetics and cytokine elaboration. Blood Cancer J 2015;5:e302.
58. Kim YG, Cho SY, Park TS, Oh SH, Yoon HJ. Therapy-related myelodysplastic syndrome/acute myeloid leukemia with del(7)(q22) in a patient with de novo AML. Ann Clin Lab Sci 2011;41:79-83.
59. Sala-Torra O, Hanna C, Loken MR, et al. Evidence of donor-derived hematologic malignancies after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2006;12:511-7.
60. Aanei CM, Flandrin P, Eloae FZ, et al. Intrinsic growth deficiencies of mesenchymal stromal cells in myelodysplastic syndromes. Stem Cells Dev 2012;21:1604-15.
61. Castells M, Thibault B, Delord JP, Couderc B. Implication of tumor microenvironment in chemoresistance: tumor-associated stromal cells protect tumor cells from cell death. Int J Mol Sci 2012;13:9545-71.
62. Flores-Figueroa E, Montesinos JJ, Flores-Guzmán P, et al. Functional analysis of myelodysplastic syndromes-derived mesenchymal stem cells. Leuk Res 2008;32:1407-16.
63. Geyh S, Oz S, Cadeddu RP, et al. Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells. Leukemia 2013;27:1841-51.
64. Hanoun M, Zhang D, Mizoguchi T, et al. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell 2014;15:365-75.
65. Medyouf H, Mossner M, Jann JC, et al. Myelodysplastic cells in patients reprogram mesenchymal stromal cells to establish a transplantable stem cell niche disease unit. Cell Stem Cell 2014;14:824-37.
66. Poon Z, Dighe N, Venkatesan SS, et al. Bone marrow MSCs in MDS: contribution towards dysfunctional hematopoiesis and potential targets for disease response to hypomethylating therapy. Leukemia 2019;33:1487-500.
67. Schepers K, Campbell TB, Passegué E. Normal and leukemic stem cell niches: insights and therapeutic opportunities. Cell Stem Cell 2015;16:254-67.
68. Duarte D, Hawkins ED, Akinduro O, et al. Inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML. Cell Stem Cell 2018;22:64-77.e6.
69. Muntión S, Ramos TL, Diez-Campelo M, et al. Microvesicles from mesenchymal stromal cells are involved in HPC-microenvironment crosstalk in myelodysplastic patients. PLoS One 2016;11:e0146722.
70. Ben-Batalla I, Schultze A, Wroblewski M, et al. Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood 2013;122:2443-52.
71. Huan J, Hornick NI, Shurtleff MJ, et al. RNA trafficking by acute myelogenous leukemia exosomes. Cancer Res 2013;73:918-29.
72. Kumar B, Garcia M, Weng L, et al. Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion. Leukemia 2018;32:575-87.
73. Doron B, Abdelhamed S, Butler JT, Hashmi SK, Horton TM, Kurre P. Transmissible ER stress reconfigures the AML bone marrow compartment. Leukemia 2019;33:918-30.
74. Marlein CR, Zaitseva L, Piddock RE, et al. NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts. Blood 2017;130:1649-60.
75. Arranz L, Sánchez-Aguilera A, Martín-Pérez D, et al. Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature 2014;512:78-81.
76. Aguayo A, Kantarjian H, Manshouri T et al. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 2000;96:2240-5.
77. Hussong JW, Rodgers GM, Shami PJ. Evidence of increased angiogenesis in patients with acute myeloid leukemia. Blood 2000;95:309-13.
78. Kurata M, Hasegawa M, Nakagawa Y, et al. Expression dynamics of drug resistance genes, multidrug resistance 1 (MDR1) and lung resistance protein (LRP) during the evolution of overt leukemia in myelodysplastic syndromes. Exp Mol Pathol 2006;81:249-54.
79. 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;146:150-7.
80. Pruneri G, Bertolini F, Soligo D, et al. Angiogenesis in myelodysplastic syndromes. Br J Cancer 1999;81:1398-401.
81. Lundberg LG, Lerner R, Sundelin P, Rogers R, Folkman J, Palmblad J. Bone marrow in polycythemia vera, chronic myelocytic leukemia, and myelofibrosis has an increased vascularity. Am J Pathol 2000;157:15-9.
82. Passaro D, Di Tullio A, Abarrategi A, et al. Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia. Cancer Cell 2017;32:324-341.e6.
83. Dias S, Hattori K, Heissig B, et al. Inhibition of both paracrine and autocrine VEGF/ VEGFR-2 signaling pathways is essential to induce long-term remission of xenotransplanted human leukemias. Proc Natl Acad Sci U S A 2001;98:10857-62.
84. Forsythe JA, Jiang BH, Iyer NV, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 1996;16:4604-13.
85. Schliemann C, Bieker R, Thoennissen N, et al. Circulating angiopoietin-2 is a strong prognostic factor in acute myeloid leukemia. Leukemia 2007;21:1901-6.
86. Rouault-Pierre K, Lopez-Onieva L, Foster K, et al. HIF-2α protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress. Cell Stem Cell 2013;13:549-63.
87. Velasco-Hernandez T, Hyrenius-Wittsten A, Rehn M, Bryder D, Cammenga J. HIF-1α can act as a tumor suppressor gene in murine acute myeloid leukemia. Blood 2014;124:3597-607.
88. Vukovic M, Guitart AV, Sepulveda C, et al. Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance. J Exp Med 2015;212:2223-34.
89. Bellamy WT, Richter L, Frutiger Y, Grogan TM. Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res 1999;59:728-33.
90. Hassan HT, Zander A. Stem cell factor as a survival and growth factor in human normal and malignant hematopoiesis. Acta Haematol 1996;95:257-62.
91. Poulos MG, Gars EJ, Gutkin MC, et al. Activation of the vascular niche supports leukemic progression and resistance to chemotherapy. Exp Hematol 2014;42:976-986.e3.
92. Ossenkoppele GJ, Breems DA, Stuessi G, et al. Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) and Swiss Group for Clinical Cancer Research (SAKK). Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS. Leukemia 2020;34:1751-9.
93. Saito Y, Uchida N, Tanaka S, et al. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol 2010;28:275-80.
94. Uy GL, Rettig MP, Motabi IH, et al. A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood 2012;119:3917-24.
95. Abraham M, Klein S, Bulvik B, et al. The CXCR4 inhibitor BL-8040 induces the apoptosis of AML blasts by downregulating ERK, BCL-2, MCL-1 and cyclin-D1 via altered miR-15a/16-1 expression. Leukemia 2017;31:2336-46.
96. Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006;12:1167-74.
97. Jacamo R, Chen Y, Wang Z, et al. Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance. Blood 2014;123:2691-702.
98. Kannan S, Sutphin RM, Hall MG, et al. Notch activation inhibits AML growth and survival: a potential therapeutic approach. J Exp Med 2013;210:321-37.
99. Laranjeira AB, Yang SX. Therapeutic target discovery and drug development in cancer stem cells for leukemia and lymphoma: from bench to the clinic. Expert Opin Drug Discov 2016;11:1071-80.
100. Granados-Principal S, Liu Y, Guevara ML, et al. Inhibition of iNOS as a novel effective targeted therapy against triple-negative breast cancer. Breast Cancer Res 2015;17:25.
101. Karp JE, Gojo I, Pili R, et al. Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias: therapy with sequential 1-beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer Res 2004;10:3577-85.
102. Ossenkoppele GJ, Stussi G, Maertens J, et al. Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK). Blood 2012;120:4706-11.
103. Müller A, Lange K, Gaiser T, et al. Expression of angiopoietin-1 and its receptor TEK in hematopoietic cells from patients with myeloid leukemia. Leuk Res 2002;26:163-8.
104. Reikvam H, Hatfield KJ, Lassalle P, Kittang AO, Ersvaer E, Bruserud Ø. Targeting the angiopoietin (Ang)/Tie-2 pathway in the crosstalk between acute myeloid leukaemia and endothelial cells: studies of Tie-2 blocking antibodies, exogenous Ang-2 and inhibition of constitutive agonistic Ang-1 release. Expert Opin Investig Drugs 2010;19:169-83.