title: CXCR4-independent rescue of the myeloproliferative defect of the Gata1low myelofibrosis mouse model by Aplidin.
abstract: The discovery of JAK2 mutations in Philadelphia-negative myeloproliferative neoplasms has prompted investigators to evaluate mutation-targeted treatments to restore hematopoietic cell functions in these diseases. However, the results of the first clinical trials with JAK2 inhibitors are not as promising as expected, prompting a search for additional drugable targets to treat these disorders. In this paper, we used the hypomorphic Gata1(low) mouse model of primary myelofibrosis (PMF), the most severe of these neoplasms, to test the hypothesis that defective marrow hemopoiesis and development of extramedullary hematopoiesis in myelofibrosis is due to insufficient p27(Kip1) activity and is treatable by Aplidin, a cyclic depsipeptide that activates p27(Kip1) in several cancer cells. Aplidin restored expression of Gata1 and p27(Kip1) in Gata1(low) hematopoietic cells, proliferation of marrow progenitor cells in vitro and maturation of megakaryocytes in vivo (reducing TGF-beta/VEGF levels released in the microenvironment by immature Gata1(low) megakaryocytes). Microvessel density, fibrosis, bone growth, and marrow cellularity were normal in Aplidin-treated mice and extramedullary hematopoiesis did not develop in liver although CXCR4 expression in Gata1(low) progenitor cells remained low. These results indicate that Aplidin effectively alters the natural history of myelofibrosis in Gata1(low) mice and suggest this drug as candidate for clinical evaluation in PMF.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Verrucci
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pancrazzi
authors.forename: Miguel
authors.initials: M
authors.lastname: Aracil
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Martelli
authors.forename: Paola
authors.initials: P
authors.lastname: Guglielmelli
authors.forename: Maria
authors.initials: M
authors.lastname: Zingariello
authors.forename: Barbara
authors.initials: B
authors.lastname: Ghinassi
authors.forename: Emanuela
authors.initials: E
authors.lastname: D'Amore
authors.forename: José
authors.initials: J
authors.lastname: Jimeno
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Vannucchi
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Migliaccio
mesh_terms: D017677:Age Distribution; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001854:Bone Marrow Cells; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D047630:Depsipeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D050982:GATA1 Transcription Factor / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D009154:Mutation; D010456:Peptides, Cyclic; D055728:Primary Myelofibrosis / Q000235:genetics* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C514936:CXCR4 protein, mouse; C493961:Cdkn1b protein, mouse; D047630:Depsipeptides; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4; D050760:Cyclin-Dependent Kinase Inhibitor p27; C098980:plitidepsin
references.citation: J Histochem Cytochem. 2007 Jul;55(7):745-52
references.pmid: 17371937
references.citation: Cell Death Differ. 2006 Nov;13(11):1968-81
references.pmid: 16543941
references.citation: Blood. 2007 Aug 15;110(4):1092-7
references.pmid: 17488875
references.citation: Ann Oncol. 2005 Oct;16(10):1667-74
references.pmid: 16014640
references.citation: Science. 2003 Oct 17;302(5644):459-62
references.pmid: 14564011
references.citation: Cancer Res. 2007 Jul 1;67(13):6417-24
references.pmid: 17616702
references.citation: Stem Cells. 2008 Aug;26(8):1920-30
references.pmid: 18511598
references.citation: Nat Med. 2000 Nov;6(11):1235-40
references.pmid: 11062534
references.citation: Leukemia. 2008 Jan;22(1):23-30
references.pmid: 17882282
references.citation: Br J Cancer. 2008 Jun 17;98(12):1966-74
references.pmid: 18521088
references.citation: Oncol Rep. 2006 Nov;16(5):1099-103
references.pmid: 17016599
references.citation: Leukemia. 2003 Jan;17(1):52-9
references.pmid: 12529660
references.citation: Cancer Chemother Pharmacol. 2006 Jan;57(1):7-14
references.pmid: 16001179
references.citation: Clin Cancer Res. 2005 Nov 1;11(21):7664-73
references.pmid: 16278386
references.citation: Cancer Cell. 2005 Jan;7(1):51-63
references.pmid: 15652749
references.citation: Mol Biol Cell. 2005 Mar;16(3):1469-80
references.pmid: 15647380
references.citation: Science. 2003 Oct 17;302(5644):445-9
references.pmid: 14564009
references.citation: Cell. 2008 Apr 18;133(2):340-53
references.pmid: 18423204
references.citation: Nat Med. 2005 Aug;11(8):886-91
references.pmid: 16025125
references.citation: Exp Hematol. 2008 Feb;36(2):158-71
references.pmid: 18206727
references.citation: Expert Rev Hematol. 2009 Jun 1;2(3):315-334
references.pmid: 20352017
references.citation: Am J Pathol. 2005 Sep;167(3):849-58
references.pmid: 16127162
references.citation: Cancer J. 2007 Nov-Dec;13(6):377-83
references.pmid: 18032975
references.citation: J Bone Miner Res. 2004 Apr;19(4):652-60
references.pmid: 15005853
references.citation: Cell. 2008 Feb 22;132(4):631-44
references.pmid: 18295580
references.citation: Br J Cancer. 2004 Jun 14;90(12):2418-24
references.pmid: 15173857
references.citation: Blood. 2005 May 1;105(9):3493-501
references.pmid: 15665119
references.citation: Mol Cancer Ther. 2007 Apr;6(4):1310-6
references.pmid: 17431109
references.citation: Mol Cell Biol. 2009 Feb;29(4):986-99
references.pmid: 19075005
references.citation: Blood. 2007 Feb 15;109(4):1460-71
references.pmid: 17038527
references.citation: N Engl J Med. 2000 Apr 27;342(17):1255-65
references.pmid: 10781623
references.citation: Proc Natl Acad Sci U S A. 1990 Jan;87(2):668-72
references.pmid: 2300555
references.citation: Exp Hematol. 2003 Nov;31(11):1104-11
references.pmid: 14585376
references.citation: J Pharmacol Exp Ther. 2008 Mar;324(3):1093-101
references.pmid: 18089842
references.citation: Blood. 2005 Dec 15;106(13):4102-13
references.pmid: 16109774
references.citation: Blood. 2009 Aug 6;114(6):1150-7
references.pmid: 19401558
references.citation: Eur J Cancer. 2002 Jul;38(10):1395-404
references.pmid: 12091072
references.citation: Cancer Res. 2008 Jul 1;68(13):5216-25
references.pmid: 18593922
references.citation: J Cell Physiol. 2010 May;223(2):460-70
references.pmid: 20112287
references.citation: Curr Opin Investig Drugs. 2009 Jun;10(6):536-42
references.pmid: 19513942
references.citation: Blood. 2009 Sep 3;114(10):2107-20
references.pmid: 19571316
references.citation: Clin Adv Hematol Oncol. 2009 May;7(5):334-42
references.pmid: 19521323
references.citation: Curr Opin Hematol. 2008 Jan;15(1):49-58
references.pmid: 18043246
references.citation: Blood. 2008 Oct 15;112(8):3026-35
references.pmid: 18669872
references.citation: Br J Cancer. 1998 Sep;78(6):739-44
references.pmid: 9743292
references.citation: Mol Cell Biol. 2009 Sep;29(18):5168-80
references.pmid: 19620289