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Background: Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) are Chronic Myeloproliferative Neoplasms (MPN) characterized by clonal myeloproliferation/myeloaccumulation without cell maturation impairment. The JAK2 V617F mutation and PRV1 gene overexpression may contribute to MPN physiopathology. We hypothesized that deregulation of the apoptotic machinery may also play a role in the pathogenesis of ET and PMF. In this study we evaluated the apoptosis-related gene and protein expression of BCL2 family members in bone marrow CD34+ hematopoietic stem cells (HSC) and peripheral blood leukocytes from ET and PMF patients. We also tested whether the gene expression results were correlated with JAK2 V617F allele burden percentage, PRV1 overexpression, and clinical and laboratory parameters.

Results: By real time PCR assay, we observed that A1, MCL1, BIK and BID, as well as A1, BCLW and BAK gene expression were increased in ET and PMF CD34+ cells respectively, while pro-apoptotic BAX and anti-apoptotic BCL2 mRNA levels were found to be lower in ET and PMF CD34+ cells respectively, in relation to controls. In patients' leukocytes, we detected an upregulation of anti-apoptotic genes A1, BCL2, BCL-XL and BCLW. In contrast, pro-apoptotic BID and BIMEL expression were downregulated in ET leukocytes. Increased BCL-XL protein expression in PMF leukocytes and decreased BID protein expression in ET leukocytes were observed by Western Blot. In ET leukocytes, we found a correlation between JAK2 V617F allele burden and BAX, BIK and BAD gene expression and between A1, BAX and BIK and PRV1 gene expression. A negative correlation between PRV1 gene expression and platelet count was observed, as well as a positive correlation between PRV1 gene expression and splenomegaly.

Conclusions: Our results suggest the participation of intrinsic apoptosis pathway in the MPN physiopathology. In addition, PRV1 and JAK2 V617F allele burden were linked to deregulation of the apoptotic machinery.

Titel:	Deregulation of apoptosis-related genes is associated with PRV1 overexpression and JAK2 V617F allele burden in Essential Thrombocythemia and Myelofibrosis.
Autor/in / Beteiligte Person:	Tognon, R ; Gasparotto, EP ; Neves, RP ; Nunes, NS ; Ferreira, AF ; Palma, PV ; Kashima, S ; Covas, DT ; Santana, M ; Souto, EX ; Zanichelli, MA ; Simões, BP ; de Souza AM ; Castro, FA
Zeitschrift:	Journal of hematology & oncology, Jg. 5 (2012-02-02), S. 2
Veröffentlichung:	[London] : Biomed Central, 2008-, 2012
Medientyp:	academicJournal
ISSN:	1756-8722 (electronic)
DOI:	10.1186/1756-8722-5-2
Schlagwort:	Adult Aged Aged, 80 and over Blotting, Western Case-Control Studies Female GPI-Linked Proteins metabolism Humans Male Middle Aged Mitochondrial Proteins Primary Myelofibrosis genetics Primary Myelofibrosis pathology RNA, Messenger genetics Real-Time Polymerase Chain Reaction Thrombocythemia, Essential genetics Thrombocythemia, Essential pathology Apoptosis Apoptosis Regulatory Proteins metabolism Isoantigens metabolism Janus Kinase 2 genetics Membrane Proteins metabolism Mutation genetics Primary Myelofibrosis metabolism Receptors, Cell Surface metabolism Thrombocythemia, Essential metabolism bcl-2-Associated X Protein metabolism bcl-Associated Death Protein metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Language: English [J Hematol Oncol] 2012 Feb 02; Vol. 5, pp. 2. <i>Date of Electronic Publication: </i>2012 Feb 02. MeSH Terms: Apoptosis* ; Apoptosis Regulatory Proteins / metabolism ; Isoantigens / metabolism ; Janus Kinase 2 / genetics ; Membrane Proteins / metabolism ; Mutation / genetics ; Primary Myelofibrosis / metabolism ; Receptors, Cell Surface / metabolism ; Thrombocythemia, Essential / metabolism ; bcl-2-Associated X Protein / metabolism ; bcl-Associated Death Protein / metabolism ; Adult ; Aged ; Aged, 80 and over ; Blotting, Western ; Case-Control Studies ; Female ; GPI-Linked Proteins / metabolism ; Humans ; Male ; Middle Aged ; Mitochondrial Proteins ; Primary Myelofibrosis / genetics ; Primary Myelofibrosis / pathology ; RNA, Messenger / genetics ; Real-Time Polymerase Chain Reaction ; Thrombocythemia, Essential / genetics ; Thrombocythemia, Essential / pathology References: Haematologica. 2004 Oct;89(10):1199-206. (PMID: 15477204) ; Hematol Oncol Clin North Am. 2009 Aug;23(4):693-708. (PMID: 19577165) ; BMC Cancer. 2011 Jan 19;11:24. (PMID: 21247487) ; Acta Clin Belg. 2009 Sep-Oct;64(5):429-33. (PMID: 19999391) ; Blood. 2005 Nov 15;106(10):3374-6. (PMID: 16081684) ; Blood. 2005 Apr 15;105(8):3303-11. (PMID: 15626746) ; N Engl J Med. 2007 Feb 1;356(5):459-68. (PMID: 17267906) ; Leuk Res. 2008 May;32(5):811-9. (PMID: 17980909) ; Leuk Res. 2008 Jan;32(1):61-9. (PMID: 17597205) ; Leukemia. 2006 Oct;20(10):1800-8. (PMID: 16871275) ; Crit Rev Clin Lab Sci. 2006;43(1):1-67. (PMID: 16531274) ; Haematologica. 2006 Mar;91(3):411-2. (PMID: 16503546) ; N Engl J Med. 2009 May 28;360(22):2289-301. (PMID: 19474426) ; Curr Cancer Drug Targets. 2008 May;8(3):207-22. (PMID: 18473734) ; PLoS Med. 2006 Jul;3(7):e270. (PMID: 16834459) ; Lancet. 2005 Mar 19-25;365(9464):1054-61. (PMID: 15781101) ; J Clin Pathol. 2011 Jan;64(1):75-82. (PMID: 21045235) ; Blood. 2009 Jun 11;113(24):6182-92. (PMID: 19387008) ; Nature. 2005 Apr 28;434(7037):1144-8. (PMID: 15793561) ; Leukemia. 2008 Jan;22(1):14-22. (PMID: 17882280) ; Curr Mol Med. 2002 Jun;2(4):381-92. (PMID: 12108949) ; Curr Pharm Des. 2010 Jan;16(1):11-33. (PMID: 20214615) ; Apoptosis. 2009 Apr;14(4):584-96. (PMID: 19156528) ; Ann Hematol. 2004 Jun;83(6):364-70. (PMID: 15034760) ; J Biol Chem. 2005 Jun 17;280(24):22788-92. (PMID: 15863514) ; Leukemia. 2005 Jul;19(7):1248-52. (PMID: 15902294) ; World J Gastroenterol. 2009 Feb 7;15(5):513-20. (PMID: 19195051) ; Blood. 2011 Aug 18;118(7):1723-35. (PMID: 21653328) ; Expert Opin Ther Targets. 2004 Oct;8(5):409-22. (PMID: 15469392) ; Br J Cancer. 2007 Sep 17;97(6):769-77. (PMID: 17726463) ; Mol Cell. 2010 Feb 12;37(3):299-310. (PMID: 20159550) ; Cancer Cell. 2005 Apr;7(4):387-97. (PMID: 15837627) ; Eur J Haematol. 2007 Dec;79(6):508-15. (PMID: 17961178) ; Trends Cell Biol. 2008 Apr;18(4):157-64. (PMID: 18314333) ; Blood. 2003 Nov 15;102(10):3569-74. (PMID: 12893745) ; Blood. 2000 Apr 15;95(8):2569-76. (PMID: 10753836) ; Eur J Haematol. 2003 Jun;70(6):358-62. (PMID: 12756017) ; Leukemia. 2009 Nov;23(11):2183-6. (PMID: 19609284) ; Mol Cell Biol. 2001 Nov;21(22):7653-62. (PMID: 11604501) ; Cancer Genet Cytogenet. 2006 May;167(1):39-42. (PMID: 16682284) ; N Engl J Med. 2005 Apr 28;352(17):1779-90. (PMID: 15858187) Substance Nomenclature: 0 (Apoptosis Regulatory Proteins) ; 0 (BAD protein, human) ; 0 (BAX protein, human) ; 0 (BIK protein, human) ; 0 (CD177 protein, human) ; 0 (GPI-Linked Proteins) ; 0 (Isoantigens) ; 0 (Membrane Proteins) ; 0 (Mitochondrial Proteins) ; 0 (RNA, Messenger) ; 0 (Receptors, Cell Surface) ; 0 (bcl-2-Associated X Protein) ; 0 (bcl-Associated Death Protein) ; EC 2.7.10.2 (JAK2 protein, human) ; EC 2.7.10.2 (Janus Kinase 2) Entry Date(s): Date Created: 20120204 Date Completed: 20120719 Latest Revision: 20211021 Update Code: 20240513 PubMed Central ID: PMC3298534

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Deregulation of apoptosis-related genes is associated with PRV1 overexpression and JAK2 V617F allele burden in Essential Thrombocythemia and Myelofibrosis.