Common mutations in ALK2/ACVR1, a multi-faceted receptor, have roles in distinct pediatric musculoskeletal and neural orphan disorders

Cytokine and Growth Factor Reviews

Volumn 27, Issue , 2016, Pages 93-104

  Pacifici, Maurizio ^a   Shore, Eileen M ^b  

^a CHILDREN S HOSPITAL OF PHILADELPHIA   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

ACVR1; ALK2; BMP signaling; Diffuse Intrinsic Pontine Gliomas; Fibrodysplasia Ossificans Progressiva; Orphan diseases

Indexed keywords

PANOBINOSTAT; ACTIVIN RECEPTOR 1; ACVR1 PROTEIN, HUMAN; TUMOR PROTEIN;

ACVR1 GENE; CLINICAL FEATURE; DISEASE ASSOCIATION; DISEASE SEVERITY; DRUG EFFECT; GENE ACTIVATION; GENE MUTATION; GENETIC DISORDER; GENETIC VARIABILITY; HUMAN; MUTATOR GENE; NONHUMAN; OSSIFICATION; OSSIFYING MYOSITIS; PONTINE GLIOMA; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; TREATMENT PLANNING; ANIMAL; BRAIN STEM TUMOR; GENETICS; GLIOMA; METABOLISM; MUTATION;

ACTIVIN RECEPTORS, TYPE I; ANIMALS; BRAIN STEM NEOPLASMS; GLIOMA; HUMANS; MUTATION; MYOSITIS OSSIFICANS; NEOPLASM PROTEINS;

EID: 84957431988     PISSN: 13596101     EISSN: 18790305     Source Type: Journal    
DOI: 10.1016/j.cytogfr.2015.12.007     Document Type: Review

References (138)

1. Schmierer B., Hill C.S. TGFβ-SMAD signal transduction: molecular specificity and functional flexibility. Nat. Rev. Mol. Cell Biol. 2007, 8:970-982.
2. Chen D., Zhao M., Mundy G.R. Bone morphogenetic proteins. Growth Factors 2004, 22:233-241.
3. Clarke T.R., Hoshiya Y., Yi S.E., Liu X., Lyons K.M., Donahoe P.K. Mullerian inhibiting substance signaling uses a bone morphogenetic protein (BMP)-like pathway mediated by ALK2 and induces SMAD6 expression. Mol. Endocrinol. 2001, 15:946-959.
4. Luo J., Tang M., Huang J., et al. TGFbeta/BMP type I receptors ALK1 and ALK2 are essential for BMP9-induced osteogenic signaling in mesenchymal stem cells. J. Biol. Chem. 2010, 285:29588-29598.
5. Zhang D., Schwarz E.M., Rosier R.N., Zuscik M.J., Puzas J.E., O'Keefe R.J. ALK2 functions as a BMP type I receptor and induces Indian hedgehog in chondrocytes during skeletal development. J. Bone Min. Res. 2003, 18:1593-1604.
6. Huse M., Chen Y.-G., Massague J., Kuriyan J. Crystal structure of the cytoplasmic domain of the type I TGFβ receptor in complex with FKBP12. Cell 1999, 96:425-436.
7. Chaikuad A., Alfano I., Kerr G., et al. Structure of the bone morphogenetic protein receptor ALK2 and implications for Fibrodysplasia Ossificans Progressiva. J. Biol. Chem. 2012, 287:36990-36998.
8. Huse M., Muir T.W., Xu L., Chen Y.G., Kuriyan J., Massague J. The TFGβ receptor activation process: an inhibitor-to-substrate binding switch. Mol. Cell 2001, 8:671-682.
9. Wang T., Li B.Y., Danielson P.D., et al. The immunophilin FKBP12 functions as a common inhibitor of the TGF-b family type I receptors. Cell 1996, 86:435-444.
10. Verschueren K., Dewulf N., Goumans M.J., et al. Expression of type I and type IB receptors for activin in midgestation mouse embryos suggests distinct functions in organogenesis. Mech. Dev. 1995, 52:109-123.
11. Mishina Y., Crombie R., Bradley A., Behringer R.R. Multiple roles for activin-like kinase-2 signaling during mouse embryogenesis. Dev. Biol. 1999, 213:314-326.
12. Rajagopal R., Dattilo L.K., Kaartinen V., et al. Functions of the type 1 BMP receptor Acvr1 (Alk2) in lens development: cell proliferation, terminal differentiation, and survival. Invest. Ophtalmol. Visual Sci. 2008, 49:4953-4960.
13. Thomas P.S., Sridurongrit S., Ruiz-Lozano P., Kaartinen V. Deficient signaling via Alk2 (Acvr1) leads to bicuspid artic valve development. PLoS One 2012, 7:e35539.
14. de Sousa Lopes S.M., Roelen B.A., Monteiro R.M., et al. BMP signaling mediated by ALK2 in the visceral endoderm is necessary for the generation of primordial germ cells in the mouse embryo. Genes Dev. 2004, 18:1838-1849.
15. Dudas M., Sridurongrit S., Nagy A., Okazaki K., Kaartinen V. Craniofacial defects in mice lacking BMP type I receptor Alk2 in neural crest cells. Mech. Dev. 2004, 121:173-182.
16. Rigueur D., Brugger S., Anbarchian T., Kim J.K., Lee Y.J., Lyons K.M. The type I BMP receptor ACVR1/ALK2 is required for chondrogenesis during development. J. Bone Min. Res. 2015, 30:733-741.
17. Copp A.J., Greene N.D., Murdoch J.N. The genetic basis of mammalian neurolation. Nat. Rev. Genet. 2003, 4:784-793.
18. Bond A.M., B O.G., Kessler J.A. The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation. Dev. Neurobiol. 2012, 72:1068-1084.
19. Le Dreau G., Marti E. The multiple activities of BMPs during spinal cord development. Cell. Mol. Life Sci. 2013, 70:4293-4305.
20. Huang X., Saint-Jeannet J.P. Induction of the neural crest and the opportunities of life on the edge. Dev. Biol. 2004, 275:1-11.
21. Kuroda H., Wessley O., De Robertis E.M. Neural induction in Xenopous: requirement for ectodermal and endomesodermal signals via chordin, noggin, beta-catenin, and cerberus. PLoS Biol. 2004, 2:e92.
22. Sauka-Spengler T., Bronner-Fraser M. Evolution of the neural crest viewed from a gene regulatory perspective. Genesis 2008, 46:673-682.
23. Anderson R.M., Lawrence A.R., Scottmann R.W., Bachiller D., Klingensmith J. Chordin and noggin promote organizing centers of forebrain development in the mouse. Development 2002, 129:4975-4987.
24. Liem K.F., Tremml G., Roelink H., Jessell T.M. Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm. Cell 1995, 82:969-979.
25. Lopez-Coviella I., Berse B., Krauss R., Ties R.S., Blusztaji J.K. Induction and maintenance of the neuronal cholinergic phenotype in the central nervous system by BMP-9. Science 2000, 289:313-316.
26. Gu Z., Reynolds E.M., Song J.J., et al. The type I serine/threonine kinase receptor ActRIA (ALK2) is required for gastrulation of the mouse embryo. Development 1999, 126:2551-2561.
27. Rowitch D.H., Kriegstein A.R. Developmental genetics of vertebrate glial-cell specification. Nature 2010, 468:214-222.
28. Mehler M.F., Mabie P.C., Zhu G., Gokhan S., Kessler J.A. Developmental changes in progenitor cell responsiveness to bone morphogenetic proteins differentially modulate progressive CNS lineage fate. Dev. Neurosci. 2000, 22:74-85.
29. Nakashima K., Yanagisawa M., Arakawa H., et al. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 1999, 284:479-482.
30. Rajan P., Panchision D.M., Newell L.F., McKay R.D. BMPs signal alternatively through a SMAD or FRAP-STAT pathway to regulate fate choice in CNS stem cells. J. Cell Biol. 2003, 161:911-921.
31. Bertrand N., Castro D.S., Guillemot F. Proneural genes and the specification of neural cell types. Nat. Rev. Neurosci. 2002, 3:517-530.
32. Nakashima K., Takizawa T., Ochiai W., et al. BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis. Proc. Natl. Acad. Sci. U. S. A. 2001, 98:5868-5873.
33. Shore E.M., Kaplan F.S. Inherited human diseases of heterotopic bone formation. Nat. Rev. Rheumatol. 2010, 6:518-527.
34. Kaplan F.S., Le Merre M., Glaser D.L., et al. Fibrodysplasia ossificans progressiva. Best Pract. Res. Clin. Rheumatol. 2008, 22:191-205.
35. Shore E., Kaplan F.S. Role of altered signal transduction in heterotopic ossification and fibrodysplasia ossificans progressiva. Curr. Osteoporos. Rep. 2011, 9:83-88.
36. Kaplan F.S., Tabas J.A., Gannon F.H., Finkel G., Hahn G.V., Zasloff M.A. The histopathology of fibrodysplasia ossificans progressiva: an endochondral process. J. Bone Joint Surg. Am. 1993, 75:220-230.
37. Lefebvre V., Bhattaram P. Vertebrate skeletogenesis. Curr. Top. Dev. Biol. 2010, 90:291-317.
38. Barnett C.P., Dugar M., Haan E.A. Late-onset variant fibrodysplasia ossificans progressiva leading to misdiagnosis of ankylosing spondylitis. Am. J. Med. Genet. 2011, 155A:1492-1495.
39. Culbert A.L., Chakkalakal S.A., Convente M.R., Lounev V.Y., Kaplan F.S., Shore E.M. Fibrodysplasia (myositis) ossificans progressiva. Genetics of Bone Biology and Skeletal Disease 2013, 375-393. Academic Press, New York. R.V. Thakker, M.P. Whyte, J.A. Eisman, T. Igarashi (Eds.).
40. Kaplan F.S., Kobori J.A., Orellana C., et al. Multi-system involvement in a severe variant of fibrodysplasia ossificans progressiva (ACVR1 c.772G > A; R258G): a report of two patients. Am. J. Med. Genet. 2015, 167:2265-2271.
41. Kaplan F.S., Xu M., Seemann P., et al. Classic and atypical Fibrodysplasia Ossificans Progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum. Mutat. 2009, 30:379-390.
42. Deirmengian G.K., Hebela N.M., O'Connell M., Glaser D.L., Shore E., Kaplan F.S. Proximal tibial osteochondromas in patients with fibrodysplasia ossificans progressiva. J. Bone Joint Surg. 2008, 90:366-374.
43. Whyte M.P., Wenkert D., Demertziz J.L., DiCarlo E.F., Westenberg E., Mumm S. Fibrodysplasia Ossificans Progress iva: middle-age onset of heterotopic ossification from a unique missense mutation (c.974G > C, p.G325A) in ACVR1. J. Bone Min. Res. 2012, 27:729-737.
44. Hebela N., Shore E., Kaplan F.S. Three pairs of monozygotic twins with fibrodysplasia ossificans progressiva. Clin. Rev. Bone Min. Met. 2005, 3:205-208.
45. Bagarova J., Vonner A.J., Armstrong K.A., et al. Constitutively active ALK2 receptor mutants require type II receptor cooperation. Mol. Cell. Biol. 2013, 33:2413-2424.
46. Fukuda T., Kohda M., Koanomata K., et al. Constitutively activated ALK2 and increased SMAD1/5 cooperatively induce bone morphogenetic protein signaling in Fibrodysplasia Ossificans Progressiva. J. Biol. Chem. 2009, 284:7149-7156.
47. Groppe J.C., Shore E., Kaplan F.S. Functional modeling of the ACVR1 (R206H) mutation in FOP. Clin. Orthop. Relat. Res. 2007, 462:87-92.
48. Shore E., Xu M., Feldman G.J., et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat. Genet. 2006, 38:525-527.
49. Ohte S., Shin M., Sasanuma H., et al. A novel mutation in ALK2, L196P, found in the most benign case of fibrodysplasia ossificans progressiva activates BMP-specific intracellular signaling equivalent to a typical mutation, R206H. Biochem. Biophys. Res. Commun. 2011, 407:213-218.
50. Gregson C.L., Hollingworth P., Williams M., et al. A novel ACVR1 mutation in the glycine/serine-rich domain foud in the most begign case of a fibrodysplasia ossificans progressiva variant reported to date. Bone 2011, 48:654-658.
51. Shen Q., Little S.C., Xu M., et al. The fibrodysplasia ossificans progressiva R206H ACVRa mutation activates BMP-independent chondrogenesis and zebrafish embryo ventralization. J. Clin. Invest. 2009, 119:3462-3472.
52. Fukuda T., Scott G., Komatsu Y., et al. Generation of a mouse with conditionally activated signaling through the BMP receptor, ALK2. Genesis 2006, 44:159-167.
53. Brunet L.J., McMahon J.A., McMahon A.P., Harland R.M. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 1998, 280:1455-1457.
54. St-Jacques B., Hammerschmidt M., McMahon A.P. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. 1999, 13:2076-2086.
55. van Dinther M., Visser N., de Gorter D.J.J., et al. ALK2 R206H mutation linked to fibrodysplasia ossificans progressiva confers constitutive activity to the BMP type I receptor and sensitizes mesenchymal cells to BMP-induced osteoblast differentiation and bone formation. J. Bone Min. Res. 2010, 25:1208-1215.
56. Culbert A.L., Chakkalakal S.A., Theosmy E.G., Breennan T.A., Kaplan F.S., Shore E.M. Alk2 regulates early chondrogenic fate in Fibrodysplasia Ossificans Progressiva heterotopic endochondral ossification. Stem Cells 2014, 32:1289-1300.
57. Chakkalakal S.A., Zhang D., Culbert A.L., et al. An Acvr1 R206H knock-in mouse has Fibrodysplasia Ossificans Progressiva. J. Bone Min. Res. 2012, 27:1746-1756.
58. Shimono K., Tung W.-E., Macolino C., et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists. Nat. Med. 2011, 17:454-460.
59. Yu P.B., Deng D.Y., Lai C.S., et al. BMP type I receptor inhibition reduces heterotopic ossification. Nat. Med. 2008, 14:1363-1369.
60. Kaplan F.S., Shore E.M., Pignolo R.J. The medical management of Fibrodysplasia Ossificans Progressiva: current treatment considerations. Clin. Proc. Intl. Clin. Consort FOP 2011, 4:1-100.
61. Simmons D.L., Botting R.M., Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol. Rev. 2004, 56:387-437.
62. DiCesare P.E., Nimni M.E., Pen L., Yazdi M., Cheung D.T. Effects of indomethacin on demineralized bone-induced heterotopic ossification in the rat. J. Orthop. Res. 1991, 9:855-861.
63. Sims N.A., Martin T.J. Coupling the activities of bone formation and resortion: a multitude of signals within the basic multicellular unit. BoneKEy Rep. 2014, 3:481.
64. Tang Y., Wu X., Lei W., et al. TGB-beta1-induced migration of bone mesenchymal stem cells couples bone resorption to formation. Nat. Med. 2009, 15:757-765.
65. Brantus J.F., Meunier P.J. Effects of intravenous etidronate and oral corticosteroids in fibrodysplasia ossificans progressiva. Clin. Orthop. 1998, 346:117-120.
66. Schuetz P., Mueller B., Christ-Crain M., Dick W., Haas H. Amino-bisphosphonates in heterotopic ossification: first experience in five consecutive cases. Spinal Cord 2005, 43:604-610.
67. Wood J., Bonjean K., Ruetz S., et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J. Pharmacol. Exp. Ther. 2002, 302:1055-1061.
68. Kronenberg H.M. Developmental regulation of the growth plate. Nature 2003, 423:332-336.
69. Kan L., Liu Y., McGuire T.L., et al. Dysregulation of local stem/progenitor cells as a common cellular mechanism for heterotopic ossification. Stem Cells 2009, 27:150-156.
70. Gannon F.H., Glaser D.L., Caron R., Thompson L.D.R., Shore E., Kaplan F.S. Mast cell involvement in fibrodysplasia ossificans progressiva. Hum. Pathol. 2001, 32:842-848.
71. Pignolo R.J., Suda R.K., Kaplan F.S. The fibrodysplasia ossificans progressiva lesion. Clin. Rev. Bone Min. Met. 2005, 5:195-200.
72. Nogginuera A., Ros J.B., Pavia C., et al. Bisphosphonates, a new treatment for glucocorticoid-induced osteoporosis in children. J. Pediatr. Endocrinol. Metab. 2003, 16:529-536.
73. Cuny G.D., Yu P.B., Laha J.K., et al. Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors. Bioorg. Med. Chem. Lett. 2008, 18:4388-4392.
74. Yu P.B., Hong C.C., Sachidanandan C., et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat. Chem. Biol. 2008, 4:33-41.
75. Mohedas A.H., Xing X., Armstrong K.A., Bullock A.N., Cuny G.D., Yu P.B. Development of an ALK2-biased BMP type I receptor kinase inhibitor. ACS Chem. Biol. 2013, 8:1291-1302.
76. Sanvitale C.E., Kerr G., Chaikuad A., et al. A new class of small molecule inhibitor of BMP signaling. PLoS One 2013, 8:e62721.
77. Evans R.M., Mangelsdorf D.J. Nuclear receptors, RXR, and the big bang. Cell 2014, 157:255-266.
78. Weston A.D., Blumberg B., Underhill T.M. Active repression by unligated retinoid receptors in development: less is sometimes more. J. Cell Biol. 2003, 161:223-228.
79. Weston A.D., Chandraratna R.A.S., Torchia J., Underhill T.M. Requirement for RAR-mediated gene repression in skeletal progenitor differentiation. J. Cell Biol. 2002, 158:39-51.
80. Pacifici M., Cossu G., Molinaro M., Tato' F. Vitamin A inhibits chondrogenesis but not myogenesis. Exp. Cell Res. 1980, 129:469-474.
81. Shimono K., Morrison T.N., Tung W.-E., et al. Inhibition of ectopic bone formation by a selective retinoic acid receptor α-agonist: a new therapy for heterotopic ossification. J. Orthop. Res. 2010, 28:271-277.
82. Hoffman L.M., Garcha K., Karamboulas K., et al. BMP action in skeletogenesis involves attenuation of retinoid signaling. J. Cell Biol. 2006, 174:101-113.
83. Weston A.D., Rosen V., Chandraratna R.A.S., Underhill T.M. Regulation of skeletal progenitor differentiation by the BMP and retinoid signaling pathways. J. Cell Biol. 2000, 148:679-690.
84. Yasuhara R., Yuasa T., Williams J.A., et al. Wnt/β-catenin and retinoic acid receptor signaling pathways interact to regulate chondrocyte function and matrix turnover. J. Biol Chem. 2010, 285:317-327.
85. Day T.F., Guo X., Garrett-Beal L., Yang Y. Wnt/β-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev. Cell 2005, 8:739-750.
86. Yasuhara R., Ohta Y., Yuasa T., et al. Roles of β-catenin signaling in phenotypic expression and proliferation of articular cartilage superficial zone cells. Lab. Invest. 2011, 91:1739-1752.
87. Hind M., Stinchcombe S. Palovarotene, a novel retinoic acid receptor gamma agonist for the treatment of emphysema. Curr. Opin. Invest. Drugs 2009, 10:1243-1250.
88. Hatsell S.J., Idone V., Alessi Wolken D.M., et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci. Trans. Med. 2015, 7:303ra137.
89. Alemna-Muench G.R., Soldevila G. When versatility matters: activins/inhibins as key regulators of immunity. Immunol. Cell Biol. 2012, 90:137-148.
90. Stiller C.A., Nectoux J. International incidence of childhood brain and spinal tumours. Int. J. Epidemiol. 1994, 23:458-464.
91. Hargrave D., Bartels U., Bouffet E. Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol. 2006, 7:241-248.
92. Sievert A.J., Fisher M.J. Pediatric low-grade gliomas. J. Child Neurol. 2009, 24:1397-1408.
93. Jansen M.H.A., van Vuurden D.G., Vandertop W.P., Kaspers G.J.L. Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology. Cancer Treat. Rev. 2012, 38:27-35.
94. Louis D.N., Perry A., Burger P., et al. International society of neuropathology-Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol. 2014, 24:429-435.
95. Epstein F., McCleary E.L. Intrinsic brain-stem tumors of childhood: surgical indications. J. Neurosurg. 1986, 64:11-15.
96. Broniscer A., Baker J.N., Baker S.J., et al. Prospective collection of tissue samples at autopsy in children with diffuse intrinsic pontine glioma. Cancer 2010, 116:4632-4637.
97. Kambhampati M., Perez J.P., Yadavilli S., et al. A standardized autopsy procurement allows for the comprehensive study of DIPG biology. Oncotarget 2015, 6:12740-12747.
98. Monje M., Mitra S.S., Freret M.E., et al. Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. Proc. Natl. Acad. Sci. U. S. A. 2011, 108:4453-4458.
99. Paugh B.S., Broniscer A., Qu C., et al. Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. J. Clin. Oncol. 2011, 29:3999-4006.
100. Jones C., Perryman L., Hargrave D. Paediatric and adult malignant glioma: close relative or distant cousins. Nat. Rev. Clin. Oncol. 2012, 9:400-413.
101. Warren K.E., Lillian K., Suuriniemi M., Wang Y., Quezado M., Meltzer P.S. Genomic aberrations in pediatric diffuse pontine gliomas. Neurol. Oncol. 2011, 14:326-332.
102. Diaz A.K., Baker S.J. The genetic signatures of pediatric high-grade glioma: no longer a one-act play. Semin. Radiat. Oncol. 2014, 24:240-247.
103. Wu G., Broniscer A., McEachron T.A., et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brain stem glioblastomas. Nat. Genet. 2012, 44:251-253.
104. Khuong-Quang D.A., Buczkowicz P., Rakopoulos P., et al. K27M mutation in histone H3: 3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 2012, 124:439-447.
105. Bender S., Tang M., Lindroth A.M., et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 2013, 24:660-672.
106. Wu G., Diaz A.K., Paugh B.S., et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat. Genet. 2014, 46:444-450.
107. Grill J., Puget S., Andreiuolo F., Philippe C., MacConaill L., Kieran M.W. Critical oncogenic mutations in newly diagnosed pediatric diffuse intrinsic pontine glioma. Pediatr. Blood Cancer 2012, 58:489-491.
108. Buczkowicz P., Hoeman C., Rakopoulos P., et al. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat. Genet. 2014, 46:451-456.
109. Fontebasso A.M., Papillon-Cavanagh S., Schwartzentruber J., et al. Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat. Genet. 2014, 46:462-466.
110. Taylor K.R., Mackay A., Truffaux N., et al. Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat. Genet. 2014, 46:457-461.
111. Shi Y., Massague' J. Mechanisms of TFG-β signaling from cell membrane to the nucleus. Cell 2003, 113:685-700.
112. Goumans M.J., Valdimarsdottir G., Itoh S., et al. Activin receptor-like kinase (ALK) 1 is an antagonistic mediator of lateral TGFβ/ALK5 signaling. Mol. Cell 2003, 12:817-828.
113. Massague J. TGFβ signaling in context. Nat. Rev. Mol. Cell Biol. 2012, 13:616-630.
114. Koyama E., Shibukawa Y., Nagayama M., et al. A distinct cohort of progenitor cells participates in synovial joint and articular cartilage formation during mouse limb skeletogenesis. Dev. Biol. 2008, 316:62-73.
115. Lounev V.Y., Ramachandran R., Wosczyna M., et al. Identification of progenitor cells that contribute to heterotopic skeletogenesis. J. Bone Joint Surg. 2009, 91:652-663.
116. Ono N., Ono W., Nagasawa T., Kronenberg H.M. A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones. Nat. Cell Biol. 2014, 16:1157-1167.
117. Wosczyna M.N., Biswas A.A., Cogswell cA.Goldhamer D.J. Multipotent progenitors resident in the skeletal muscle interstitium exhibit robust BMP-dependent osteogenic activity and mediate heterotopic ossification. J. Bone Min. Res. 2012, 27:1004-1017.
118. Monje M., Mitra S.S., Freret M.E., et al. Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. Proc. Natl. Acad. Sci. U. S. A. 2011, 108:4453-4458.
119. Ma Y.H., Mentlein R., Knerlich F., Kruse M.L., Medhdorn H.M., Held-Feindt J. Expression of stem cell markers in human astrocytomas of different WHO grades. J. Neurooncol. 2008, 86:31-45.
120. Ben-Porath I., Thomson M.W., Carey V.J., et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat. Genet. 2008, 40:499-507.
121. Lu Q.R., Yuk D., Alberta J.A., et al. Sonic hedgehog-regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron 2000, 25:317-329.
122. Guo X., Wang X.-F. Signaling cross-talk between TFG-β/BMP and other pathways. Cell Res. 2009, 19:71-88.
123. Maurya A.K., Tan H.L., Souren M., Wang X., Wittbrodt J., Ingham P.W. Integration of hedgehog and BMP signaling by the engrailed2a gene in the zebrafish myotome. Development 2011, 138:755-765.
124. Saratsis A.M., Kambhampati M., Snyder K., et al. Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma revelas distinct molecular subtypes. Acta Neuropathol. 2014, 127:881-895.
125. Brardwaj G., Murdoch B., Wu D.Y., et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat. Immunol. 2001, 2:172-180.
126. Timmer J.R., Wang C., Niswander L. BMP signaling patterns the dorsal and intermediate neural tube via regulation of homeobox and helix-loop-helix transcription factors. Development 2002, 129:2459-2472.
127. Wacker S.A., NcNully C.L., Durston A.J. The initiation of Hox gene expression in Xenopus laevis is controlled by Brachyury and BMP-4. Dev. Biol. 2004, 266:123-137.
128. Costa B.M., Smith J.S., Chen Y., et al. Reversing HOXA9 oncogene activation by PI3K inhibition: epigenetic mechanisms and prognostic significance in human glioblastoma. Cancer Res. 2010, 70:453-462.
129. Gaspar N., Marrshall L., Perryman L., et al. MGMT-independent temozolomide resistance in pediatric glioblastoma cells associatd with a PI3-kinase-mediated HOX/stem cell gene signature. Cancer Res. 2010, 70:9243-9252.
130. Murat A., Migliavacca E., Gorlia T., et al. Stem cell-related self-renewal signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J. Clin. Oncol. 2008, 26:3015-3024.
131. Stupp R., Hegi M.E., van den Bent M.J., et al. Changing paradigms-an update on the multidisciplinary management of malignant glioma. Oncologist 2006, 11:165-180.
132. Bielen A., Perryman L., Box G.M., et al. Enhanced efficacy of IGF1R inhibition in pediatric glioblastoma by combinatorial targeting of PDGFRα/β. Mol. Cancer Ther. 2011, 10:1407-1418.
133. Grasso C.S., Tang Y., Truffaux N., et al. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat. Med. 2015, 21:555-559.
134. Kan L., Kitterman J.A., Procissi D., et al. CNS demyelination in fibrodysplasia ossificans progressiva. J. Neurol. 2012, 259:2644-2655.
135. Kitterman J.A., Strober J.B., Kan L., et al. Eurological symptoms in individuals with fibrodysplasia ossificans progressiva. J. Neurol. 2012, 259:2636-2643.
136. Bertamino M., Severino M., Schiaffino M.C., et al. New insights into central nervous system involvement in FOP: case report and review of the literature. Am. J. Med. Genet. 2015, 167A:2817-2821.
137. Koyama E., Golden E.B., Kirsch T., et al. Retinoid signaling is required for chondrocyte maturation and endochondral bone formation during limb skeletogenesis. Dev. Biol. 1999, 208:375-391.
138. Groppe J.C., Wu J., Shore E.M., Kaplan F.S. In vitro analyses of the dysregulated R206H ALK2 kinase-FKBP12 interaction associated with heterotopic ossification in FOP. Cells Tissues Organs 2011, 194(2-4):291-295.