Myelodysplasia is in the niche: Novel concepts and emerging therapies

Leukemia

Volumn 29, Issue 2, 2015, Pages 259-268

  Bulycheva, E ^a   Rauner, M ^a   Medyouf, H ^b   Theurl, I ^c   Bornhauser M ^a,d   Hofbauer, L C ^a,d   Platzbecker, U ^a  

^a UNIVERSITY HOSPITAL CARL GUSTAV CARUS   (Germany)

^b INSTITUTE FOR TUMOR BIOLOGY AND EXPERIMENTAL THERAPY   (Germany)

^c INNSBRUCK MEDICAL UNIVERSITY   (Austria)

^d CENTER FOR REGENERATIVE THERAPIES DRESDEN   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

5 AZA 2' DEOXYCYTIDINE; AZACITIDINE; CELL ADHESION MOLECULE; ERYTHROPOIETIN; ESTROGEN; LENALIDOMIDE; LUSPATERCEPT; PARATHYROID HORMONE; SOTATERCEPT; CYTOKINE; IRON;

ACUTE GRANULOCYTIC LEUKEMIA; ARTICLE; BONE METABOLISM; CELL DIFFERENTIATION; CELL RENEWAL; EPIGENETICS; HEMATOPOIESIS; HUMAN; IRON CHELATION; IRON METABOLISM; IRON OVERLOAD; MESENCHYMAL STEM CELL; MYELODYSPLASTIC SYNDROME; NONHUMAN; OSTEOBLAST; PATHOGENESIS; PRIORITY JOURNAL; PROGENY; STEM CELL NICHE; ANIMAL; BONE MARROW; CHEMISTRY; CYTOLOGY; DISEASE COURSE; GENETIC EPIGENESIS; HEMATOPOIETIC STEM CELL; MESENCHYMAL STROMA CELL; METABOLISM; MYELODYSPLASTIC SYNDROMES; PATHOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; BONE MARROW; CYTOKINES; DISEASE PROGRESSION; EPIGENESIS, GENETIC; ERYTHROPOIETIN; HEMATOPOIETIC STEM CELLS; HUMANS; IRON; IRON OVERLOAD; MESENCHYMAL STROMAL CELLS; MYELODYSPLASTIC SYNDROMES; OSTEOBLASTS; PARATHYROID HORMONE; SIGNAL TRANSDUCTION;

EID: 84922552888     PISSN: 08876924     EISSN: 14765551     Source Type: Journal    
DOI: 10.1038/leu.2014.325     Document Type: Article

References (120)

1. Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature 2014; 505: 327-334.
2. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 2003; 425: 841-846.
3. Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, MacArthur BD, Lira SA et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010; 466: 829-U59.
4. Visnjic D, Kalajzic Z, Rowe DW, Katavic V, Lorenzo J, Aguila HL. Hematopoiesis is severely altered in mice with an induced osteoblast de ficiency. Blood 2004; 103: 3258-3264.
5. Adams GB, Chabner KT, Alley IR, Olson DP, Szczepiorkowski ZM, Poznansky MC et al. Stem cell engraftment at the endosteal niche is specified by the calciumsensing receptor. Nature 2006; 439: 599-603.
6. Pinho S, Lacombe J, Hanoun M, Mizoguchi T, Bruns I, Kunisaki Y et al. PDGFR alpha and CD51 mark human Nestin(+) sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion. J Exp Med 2013; 210: 1351-1367.
7. Greenbaum A, Hsu YMS, Day RB, Schuettpelz LG, Christopher MJ, Borgerding JN et al. CXCL12 in early mesenchymal progenitors is. required for haematopoietic stem-cell maintenance. Nature 2013; 495: 227-230.
8. Mizoguchi T, Pinho S, Ahmed J, Kunisaki Y, Hanoun M, Mendelson A et al. Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development. Dev Cell 2014; 29: 340-349.
9. Lymperi S, Ersek A, Ferraro F, Dazzi F, Horwood NJ. Inhibition of osteoclast function reduces hematopoietic stem cell numbers in vivo. Blood 2011; 117: 1540-1549.
10. Miyamoto K, Yoshida S, Kawasumi M, Hashimoto K, Kimura T, Sato Y et al. Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization. J Exp Med 2011; 208: 2175-2181.
11. Soki FN, Li X, Berry J, Koh A, Sinder BP, Qian X et al. The effects of zoledronic acid in the bone and vasculature support of hematopoietic stem cell niches. J Cell Biochem 2013; 114: 67-78.
12. Mansour A, Abou-Ezzi G, Sitnicka E, Jacobsen SEW, Wakkach A, Blin-Wakkach C. Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow. J Exp Med 2012; 209: 537-549.
13. Ludin A, Itkin T, Gur-Cohen S, Mildner A, Shezen E, Golan K et al. Monocytesmacrophages that express alpha-smooth muscle actin preserve primitive hematopoietic cells in the bone marrow. Nat Immunol 2012; 13: 1072-1082.
14. Winkler IG, Sims NA, Pettit AR, Barbier V, Nowlan B, Helwani F et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood 2010; 116: 4815-4828.
15. Hoggatt J, Singh P, Sampath J, Pelus LM. Prostaglandin E-2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood 2009; 113: 5444-5455.
16. Cho SW, Soki FN, Koh AJ, Eber MR, Entezami P, Park SI et al. Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone. Proc Natl Acad Sci USA 2014; 111: 1545-1550.
17. Siegel G, Kluba T, Hermanutz-Klein U, Bieback K, Northoff H, Schafer R. Phenotype, donor age and gender affect function of human bone marrow derived mesenchymal stromal cells. BMC Med 2013, 11.
18. Maijenburg MW, Kleijer M, Vermeul K, Mul EPJ, van Alphen FPJ, van der Schoot CE et al. The composition of the mesenchymal stromal cell compartment in human bone marrow changes during development and aging. Haematologica 2012; 97: 179-183.
19. Tormin A, Li O, Brune JC, Walsh S, Schutz B, Ehinger M et al. CD146 expression on primary nonhematopoietic bone marrow stem cells is correlated with in situ localization. Blood 2011; 117 : 5067-5077.
20. Ye L, Fan ZP, Yu B, Chang J, Al Hezaimi K, Zhou XD et al. Histone demethylases KDM4B and KDM6B promote osteogenic differentiation of human MSCs. Cell Stem Cell 2012; 11: 50-61.
21. Choumerianou DM, Martimianaki G, Stiakaki E, Kalmanti L, Kalmanti M, Dimitriou H. Comparative study of stemness characteristics of mesenchymal cells from bone marrow of children and adults. Cytotherapy 2010; 12: 881-887.
22. Jung YG, Song JH, Shiozawa Y, Wang JC, Wang Z, Williams B et al. Hematopoietic stem cells regulate mesenchymal stromal cell induction into osteoblasts thereby participating in the formation of the stem cell niche. Stem Cells 2008; 26: 2042-2051.
23. Whitfield JF. Parathyroid hormone (PTH) and hematopoiesis: new support for some old observations. J Cell Biochem 2005; 96: 278-284.
24. Petrova NV, Svinareva DA, Nifontova IN, Momotyuk KS, Savchenko VG, Drize NI. Stromal regulation of hemopoietic stem cells in long-term human bone marrow tissue cultures under the effect of parathyroid hormone. Bull Exp Biol Med 2006; 142: 527-530.
25. Lee JH, Hwang KJ, Kim MY, Lim YJ, Seol IJ, Jin HJ et al. Human parathyroid hormone increases the mRNA expression of the IGF system and hematopoietic growth factors in osteoblasts, but does not influence expression in mesenchymal stem cells. J Pediatr Hematol Oncol 2012; 34: 491-496.
26. Cho SW, Pirih FQ, Koh AJ, Michalski M, Eber MR, Ritchie K et al. The soluble interleukin-6 receptor is a mediator of hematopoietic and skeletal actions of parathyroid hormone. J Biol Chem 2013; 288: 6814-6825.
27. Krishnan V, Bryant HU, MacDougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest 2006; 116: 1202-1209.
28. Boland GM, Perkins G, Hall DJ, Tuan RS. Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells. J Cell Biochem 2004; 93: 1210-1230.
29. Glass DA, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell 2005; 8 : 751-764.
30. Baksh D, Tuan RS. Canonical and non-canonical wnts differentially affect the development potential of primary isolate of human bone marrow mesenchymal stem cells. J Cell Physiol 2007; 212: 817-826.
31. Cho SW, Yang JY, Sun HJ, Jung JY, Her SJ, Cho HY et al. Wnt inhibitory factor (WIF)-1 inhibits osteoblastic differentiation in mouse embryonic mesenchymal cells. Bone 2009; 44: 1069-1077.
32. Maeda K, Kobayashi Y, Udagawa N, Uehara S, Ishihara A, Mizoguchi T et al. Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat Med 2012; 18: 405-U166.
33. Churchman SM, Ponchel F, Boxall SA, Cuthbert R, Kouroupis D, Roshdy T et al. Transcriptional profile of native CD271+ multipotential stromal cells: evidence for multiple fates, with prominent osteogenic and wnt pathway signaling activity. Arthritis Rheum 2012; 64: 2632-2643.
34. Vukicevic S, Grgurevic L. BMP-6 and mesenchymal stem cell differentiation. Cytokine Growth Factor Rev 2009; 20: 441-448.
35. Simic P, Culej JB, Orlic I, Grgurevic L, Draca N, Spaventi R et al. Systemically administered bone morphogenetic protein-6 restores bone in aged ovariectomized rats by increasing bone formation and suppressing bone resorption. J Biol Chem 2006; 281: 25509-25521.
36. Seib FP, Franke M, Jing D, Werner C, Bornhauser M. Endogenous bone morphogenetic proteins in human bone marrow-derived multipotent mesenchymal stromal cells. Eur J Cell Biol 2009; 88: 257-271.
37. del Toro R, Mendez-Ferrer S. Autonomic regulation of hematopoiesis and cancer. Haematologica 2013; 98: 1663-1666.
38. Shiozawa Y, Jung YH, Ziegler AM, Pedersen EA, Wang JH, Wang Z et al. Erythropoietin couples hematopoiesis with bone formation. Plos One 2010; 5: e10853.
39. Sun HL, Jung YH, Shiozawa Y, Taichman RS, Krebsbach PH. Erythropoietin modulates the structure of bone morphogenetic protein 2-engineered cranial bone. Tissue Eng Pt A 2012; 18: 2095-2105.
40. Kim J, Jung YH, Sun HL, Joseph J, Mishra A, Shiozawa Y et al. Erythropoietin mediated bone formation is regulated by mTOR signaling. J Cell Biochem 2012; 113: 220-228.
41. Singbrant S, Russell MR, Jovic T, Liddicoat B, Izon DJ, Purton LE et al. Erythropoietin couples erythropoiesis, B-lymphopoiesis, and bone homeostasis within the bone marrow microenvironment. Blood 2011; 117: 5631-5642.
42. Nair AM, Tsai YT, Shah KM, Shen JH, Weng H, Zhou J et al. The effect of erythropoietin on autologous stem cell-mediated bone regeneration. Biomaterials 2013; 34: 7364-7371.
43. Koh SH, Noh MY, Cho GW, Kim KS, Kim SH. Erythropoietin increases the motility of human bone marrow-multipotent stromal cells (hBM-MSCs) and enhances the production of neurotrophic factors from hBM-MSCs. Stem Cells Dev 2009; 18: 411-421.
44. Rankin EB, Wu C, Khatri R, Wilson TLS, Andersen R, Araldi E et al. The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell 2012; 149: 63-74.
45. Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 2013; 122: 3616-3627.
46. Malcovati L, Papaemmanuil E, Bowen DT, Boultwood J, Della Porta MG, Pascutto C et al. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood 2011; 118: 6239-6246.
47. Starczynowski DT, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, Muranyi A et al. Identification of miR-145 and miR-146a as mediators of the 5q-syndrome phenotype. Nat Med 2010; 16: 49-U84.
48. Watanabe-Okochi N, Kitaura J, Ono R, Harada H, Harada Y, Komeno Y et al. AML1 mutations induced MDS and MDS/AML in a mouse BMT model. Blood 2008; 111: 4297-4308.
49. Grisendi S, Bernardi R, Rossi M, Cheng K, Khandker L, Manova K et al. Role of nucleophosmin in embryonic development and tumorigenesis. Nature 2005; 437: 147-153.
50. Buonamici S, Li DL, Chi YQ, Zhao R, Wang XR, Brace L et al. EVI1 induces myelodysplastic syndrome in mice. J Clin Invest 2004; 114: 713-719.
51. Lin YW, Slape C, Zhang ZH, Aplan PD. NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia. Blood 2005; 106: 287-295.
52. Muto T, Sashida G, Oshima M, Wendt GR, Mochizuki-Kashio M, Nagata Y et al. Concurrent loss of Ezh2 and Tet2 cooperates in the pathogenesis of myelodysplastic disorders. J Exp Med 2013; 210: 2627-2639.
53. Abdel-Wahab O, Gao J, Adli M, Dey A, Trimarchi T, Chung YR et al. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. J Exp Med 2013; 210: 2641-2659.
54. Nagamachi A, Matsui H, Asou H, Ozaki Y, Aki D, Kanai A et al. Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7. Cancer Cell 2013; 24: 305-317.
55. Lane SW, Sykes SM, Al-Shahrour F, Shterental S, Paktinat M, Lo Celso C et al. The Apc(min) mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS. Blood 2010; 115: 3489-3497.
56. Raaijmakers MHGP, Mukherjee S, Guo SQ, Zhang SY, Kobayashi T, Schoonmaker JA et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 2010; 464: 852-U58.
57. Santamaria C, Muntion S, Roson B, Blanco B, Lopez-Villar O, Carrancio S et al. Impaired expression of DICER, DROSHA, SBDS and some microRNAs in mesenchymal stromal cells from myelodysplastic syndrome patients. Haematologica 2012; 97: 1218-1224.
58. Medyouf H, Mossner M, Jann JC, Nolte F, Raffel S, Herrmann C et al. Myelodysplastic cells in patients reprogramm mesenchymal stromal cells to establish a transplantable stem cell niche disease unit. Cell Stem Cell 2014; 14: 824-837.
59. Martin MG, Welch JS, Uy GL, Fehniger TA, Kulkarni S, Duncavage EJ et al. Limited engraftment of low-risk myelodysplastic syndrome cells in NOD/SCID gamma-C chain knockout mice. Leukemia 2010; 24: 1662-1664.
60. Li X, Deeg HJ. Murine xenogeneic models of myelodysplastic syndrome: an essential role for stroma cells. Exp Hemat 2014; 42: 4-10.
61. Mellibovsky L, Diez A, Serrano S, Aubia J, PerezVila E, Marinoso ML et al. Bone remodeling alterations in myelodysplastic syndrome. Bone 1996; 19: 401-405.
62. Flores-Figueroa E, Arana-Trejo RM, Gutierrez-Espindola G, Perez-Cabrera A, Mayani H. Mesenchymal stem cells in myelodysplastic syndromes: phenotypic and cytogenetic characterization. Leukemia Res 2005; 29: 215-224.
63. Flores-Figueroa E, Montesinos JJ, Flores-Guzman P, Gutierrez-Espindola G, Arana-Trejo RM, Castillo-Medina S et al. Functional analysis of myelodysplastic syndromes-derived mesenchymal stem cells. Leukemia Res 2008; 32: 1407-1416.
64. Soenen-Cornu V, Tourino C, Bonnet ML, Guillier M, Flamant S, Kotb R et al. Mesenchymal cells generated from patients with myelodysplastic syndromes are devoid of chromosomal clonal markers and support short- and long-term hematopoiesis in vitro. Oncogene 2005; 24: 2441-2448.
65. Gayh S, Cadeddu RP, Fröbel J. MDS-derived mesenchymal stromal cells are phenotypically, structurally and epigenetically altered resulting in insufficient stromal support for CD34+ HSPC. Leuk Res 2013; 37: P-230 Ref Type: Abstract.
66. Zhao ZG, Xu W, Yu HP, Fang BL, Wu SH, Li F et al. Functional characteristics of mesenchymal stem cells derived from bone marrow of patients with myelodysplastic syndromes. Cancer Lett 2012; 317: 136-143.
67. Frisch BJ, Ashton JM, Xing LP, Becker MW, Jordan CT, Calvi LM. Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemia. Blood 2012; 119: 540-550.
68. Campioni D, Moretti S, Ferrari L, Punturieri M, Castoldi GL, Lanza F. Immunophenotypic heterogeneity of bone marrow-derived mesenchymal stromal cells from patients with hematologic disorders: correlation with bone marrow microenvironment. Haematologica 2006; 91: 364-368.
69. Ferrer RA, Wobus M, List C, Wehner R, Schonefeldt C, Brocard B et al. Mesenchymal stromal cells from patients with myelodyplastic syndrome display distinct functional alterations that are modulated by lenalidomide. Haematologica 2013; 98: 1677-1685.
70. Aanei CM, Flandrin P, Eloae FZ, Carasevici E, Guyotat D, Wattel E et al. Intrinsic growth deficiencies of mesenchymal stromal cells in myelodysplastic syndromes. Stem Cells Dev 2012; 21: 1604-1615.
71. Flores-Figueroa E, Varma S, Montgomery K, Greenberg PL, Gratzinger D. Distinctive contact between CD34+ hematopoietic progenitors and CXCL12+ CD271+ mesenchymal stromal cells in benign and myelodysplastic bone marrow. Lab Invest 2012; 92: 1330-1341.
72. Ximeri M, Galanopoulos A, Klaus M, Parcharidou A, Giannikou K, Psyllaki M et al. Effect of lenalidomide therapy on hematopoiesis of patients with myelodysplastic syndrome associated with chromosome 5q deletion. Haematologica 2010; 95: 406-414.
73. Pimenova MA, Kokhno AV, Domracheva E, Drize NI, Manakova T, Konnova M et al. Chromosomal analysis of hematopoietic and stromal progenitor cells in patients with myelodysplastic syndrome (MDS). Leuk Res 2013; 37: P-254 Ref Type: Abstract.
74. Blau O, Baldus CD, Hofmann WK, Thiel G, Nolte F, Burmeister T et al. Mesenchymal stromal cells of myelodysplastic syndrome and acute myeloid leukemia patients have distinct genetic abnormalities compared with leukemic blasts. Blood 2011; 118: 5583-5592.
75. de Oliveira FM, Lucena-Araujo AR, Favarin MD, Palma PVB, Rego EM, Falcao RP et al. Differential expression of AURKA and AURKB genes in bone marrow stromal mesenchymal cells of myelodysplastic syndrome: correlation with G-banding analysis and FISH. Exp Hematol 2013; 41: 198-208.
76. Iwata M, Pillai M, Ramakrishnan A, Hackman RC, Deeg HJ, Opdenakker G et al. Reduced expression of inducible gelatinase B/matrix metalloproteinase-9 in monocytes from patients with myelodysplastic syndrome: correlation of inducible levels with the percentage of cytogenetically marked cells and with marrow cellularity. Blood 2007; 109: 85-92.
77. Flores-Figueroa E, Gutierrez-Espindola G, Montesinos JJ, Arana-Trejo RM, Mayani H. In vitro characterization of hematopoietic microenvironment cells from patients with myelodysplastic syndrome. Leuk Res 2002; 26: 677-686.
78. Matsuoka A, Tochigi A, Kishimoto M, Nakahara T, Kondo T, Tsujioka T et al. Lenalidomide induces cell death in an MDS-derived cell line with deletion of chromosome 5q by inhibition of cytokinesis. Leukemia 2010; 24: 748-755.
79. Ishibashi M, Tamura H, Ogata K. Disease progression mechanism in myelodysplastic syndromes: insight into the role of the microenvironment. Leuk Res 2011; 35: 1449-1452.
80. Reins J, Mossner M, Neumann M, Platzbecker U, Schumann C, Thiel E et al. Transcriptional down-regulation of the Wnt antagonist SFRP1 in haematopoietic cells of patients with different risk types of MDS. Leuk Res 2010; 34: 1610-1616.
81. Wang H, Fan R, Wang XQ, Wu DP, Lin GW, Xu Y et al. Methylation of Wnt antagonist genes: a useful prognostic marker for myelodysplastic syndrome. Ann Hematol 2013; 92: 199-209.
82. Pavlaki KI, Kastrinaki MC, Batsali A, Demetriadou A, Velegraki M, Mavroudi I et al. Impaired Wnt-pathway signalling and reduced expression of senescenceassociated markers in bone marrow mesenchymal stem cells of patients with myelodysplastic syndromes. Blood 2011; 118: 125-126.
83. Luis TC, Ichii M, Brugman MH, Kincade P, Staal FJT. Wnt signaling strength regulates normal hematopoiesis and its deregulation is involved in leukemia development. Leukemia 2012; 26: 414-421.
84. Schaniel C, Sirabella D, Qiu JJ, Niu XH, Lemischka IR, Moore KA. Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells. Blood 2011; 118: 2420-2429.
85. Renstrom J, Istvanffy R, Gauthier K, Shimono A, Mages J, Jardon-Alvarez A et al. Secreted frizzled-related protein 1 extrinsically regulates cycling activity and maintenance of hematopoietic stem cells. Cell Stem Cell 2009; 5: 157-167.
86. Fleming HE, Janzen V, Lo Celso C, Guo J, Leahy KM, Kronenberg HM et al. Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell 2008; 2: 274-283.
87. Lane SW, Wang YZJ, Lo Celso C, Ragu C, Bullinger L, Sykes SM et al. Differential niche and Wnt requirements during acute myeloid leukemia progression. Blood 2011; 118: 2849-2856.
88. Qu ZH, Zhang XL, Tang TT, Dai KR. Promotion of osteogenesis through betacatenin signaling by desferrioxamine. Biochem Biophys Res Commun 2008; 370: 332-337.
89. Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N et al. Leukaemogenesis induced by an activating beta-catenin mutation in osteoblasts. Nature 2014; 506: 240-244.
90. Park S, Grabar S, Kelaidi C, Beyne-Rauzy O, Picard F, Bardet V et al. Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience. Blood 2008; 111: 574-582.
91. Frisan E, Pawlikowska P, Pierre-Eugene C, Viallon V, Gibault L, Park S et al. p-ERK1/2 is a predictive factor of response to erythropoiesis-stimulating agents in low/int-1 myelodysplastic syndromes. Haematologica 2010; 95: 1964-1968.
92. Forejtnikova H, Vieillevoye M, Zermati Y, Lambert M, Pellegrino RM, Guihard S et al. Transferrin receptor 2 is a component of the erythropoietin receptor complex and is required for efficient erythropoiesis. Blood 2010; 116: 5357-5367.
93. Guggenbuhl P, Filmon R, Mabilleau G, Basle MF, Chappard D. Iron inhibits hydroxyapatite crystal growth in vitro. Metabolism 2008; 57: 903-910.
94. Yang Q, Jian JL, Abramson SB, Huang X. Inhibitory effects of iron on bone morphogenetic protein 2-induced osteoblastogenesis. J Bone Miner Res 2011; 26: 1188-1196.
95. Guggenbuhl P, Fergelot P, Doyard M, Libouban H, Roth MP, Gallois Y et al. Bone status in a mouse model of genetic hemochromatosis. Osteoporos Int 2011; 22: 2313-2319.
96. Zarjou A, Jeney V, Arosio P, Poli M, Zavaczki E, Balla G et al. Ferritin ferroxidase activity: a potent inhibitor of osteogenesis. J Bone Miner Res 2010; 25: 164-172.
97. Tsay J, Yang ZW, Ross FP, Cunningham-Rundles S, Lin H, Coleman R et al. Bone loss caused by iron overload in a murine model: importance of oxidative stress. Blood 2010; 116: 2582-2589.
98. Jia P, Xu YJ, Zhang ZL, Li K, Li BY, Zhang W et al. Ferric ion could facilitate osteoclast differentiation and bone resorption through the production of reactive oxygen species. J Orthop Res 2012; 30: 1843-1852.
99. Liu G, Men P, Kenner GH, Miller SC. Therapeutic effects of an oral chelator targeting skeletal tissue damage in experimental postmenopausal osteoporosis in rats. Hemoglobin 2008; 32: 181-190.
100. Lee NK, Choi YG, Baik JY, Han SY, Jeong DW, Bae YS et al. A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood 2005; 106: 852-859.
101. Murphy PT, Mitra S, Gleeson M, Desmond R, Swinkels DW. Urinary hepcidin excretion in patients with low grade myelodysplastic syndrome. Br J Haematol 2009; 144: 451-452.
102. Winder A, Lefkowitz R, Ghoti H, Leiba M, Ganz T, Nemeth E et al. Urinary hepcidin excretion in patients with myelodysplastic syndrome and myelofibrosis. Br J Haematol 2008; 142: 669-671.
103. Ambaglio I, Malcovati L, Papaemmanuil E, Laarakkers CM, Della Porta MG, Galli A et al. Inappropriately low hepcidin levels in patients with myelodysplastic syndrome carrying a somatic mutation of SF3B1. Haematologica 2013; 98: 420-423.
104. Breda L, Ghoti H, Rivella S, Rechavi G, Cabantchik I, Rachmilewitz E. Expression of genes regulating iron metabolism in hepatocyte cell-line HepG2 induced by sera from MDS patients. Blood 2007; 110: 225B-226BB.
105. Masala E, Valencia A, Buchi F, Nosi D, Spinelli E, Gozzini A et al. Hypermethylation of Wnt antagonist gene promoters and activation of Wnt pathway in myelodysplastic marrow cells. Leuk Res 2012; 36: 1290-1295.
106. Delgado-Calle J, Arozamena J, Perez-Lopez J, Bolado-Carrancio A, Sanudo C, Agudo G et al. Role of BMPs in the regulation of sclerostin as revealed by an epigenetic modifi er of human bone cells. Mol Cell Endocrinol 2013; 369: 27-34.
107. Dussiot M, Maciel TT, Fricot A, Chartier C, Negre O, Veiga J et al. An activin receptor IIA ligand trap corrects ineffective erythropoiesis in beta-thalassemia. Nat Med 2014; 20: 398-+.
108. Lotinun S, Pearsall RS, Davies MV, Marvell TH, Monnell TE, Ucran J et al. A soluble activin receptor Type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys. Bone 2010; 46: 1082-1088.
109. Mulivor AW, Barbosa D, Kumar R, Sherman ML, Seehra J, Pearsall RS. RAP-011, a soluble activin receptor type IIa murine IgG-Fc fusion protein, prevents chemotherapy induced anemia. Blood 2009; 114: 72.
110. Ruckle J, Jacobs M, Kramer W, Pearsall AE, Kumar R, Underwood KW et al. Single-dose, randomized, double-blind, placebo-controlled study of ACE-011 (ActRIIA-IgG1) in postmenopausal women. J Bone Miner Res 2009; 24: 744-752.
111. Abdulkadyrov KM, Salogub GN, Khuazheva NK, Sherman ML, Laadem A, Bager R et al. Sotatercept in patients with osteolytic lesions of multiple myeloma. Br J Haemat 2014; 165: 814-823.
112. Carrancio S, Markovics J, Wong P, Leisten J, Castiglioni P, Groza MC et al. An activin receptor IIA ligand trap promotes erythropoiesis resulting in a rapid induction of red blood cells and haemoglobin. Br J Haematol 2014; 165: 870-882.
113. Iancu-Rubin C, Mosoyan G, Wang JP, Kraus T, Sung V, Hoffman R. Stromal cell-mediated inhibition of erythropoiesis can be attenuated by sotatercept (ACE-011), an activin receptor type II ligand trap. Exp Hematol 2013; 41: 155-166.
114. Suragani RN, Cadena SM, Cawley SM, Sako D, Mitchell D Li R et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med 2014; 20: 408-414.
115. th Congress of European Hematology Association, S1296 2014; Ref Type: Abstract.
116. Gattermann N, Finelli C, Della Porta M, Fenaux P, Stadler M, Guerci-Bresler A et al. Hematologic responses to deferasirox therapy in transfusion-dependent patients with myelodysplastic syndromes. Haematologica 2012; 97: 1364-1371.
117. Lu WY, Zhao MF, Rajbhandary S, Xie F, Chai X, Mu J et al. Free iron catalyzes oxidative damage to hematopoietic cells/mesenchymal stem cells in vitro and suppresses hematopoiesis in iron overload patients. Eur J Haematol 2013; 91: 249-261.
118. Li HH, Rybicki AC, Suzuka SM, von Bonsdorff L, Breuer W, Hall CB et al. Transferrin therapy ameliorates disease in beta-thalassemic mice. Nat Med 2010; 16: 177-U80.
119. Nicolas G, Viatte L, Lou DQ, Bennoun M, Beaumont C, Kahn A et al. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet 2003; 34: 97-101.
120. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest 2007; 117: 1933-1939.