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. 2007 Jan;99(1):57–63.

Overexpression of the local bone marrow renin-angiotensin system in acute myeloid leukemia.

Yavuz Beyazit 1, Salih Aksu 1, Ibrahim C Haznedaroglu 1, Murat Kekilli 1, Muge Misirlioglu 1, Serdar Tuncer 1, Jale Karakaya 1, Ebru Koca 1, Yahya Buyukasik 1, Nilgun Sayinalp 1, Hakan Goker 1
PMCID: PMC2569610  PMID: 17304969

Abstract

OBJECTIVES: Local bone marrow renin-angiotensin system (RAS) is an autocrine-paracrine system affecting hematopoiesis. Angiotensin II stimulates the proliferation of bone marrow and umbilical cord blood hematopoietic progenitors. Angiotensin-converting enzyme (ACE) hyperfunction may lead to the acceleration of negative hematopoietic regulator peptide, AcSDKP, metabolism, which in turn lowers its level in the bone marrow microenvironment, finally removing the antiproliferative effect of AcSDKP on the hematopoietic cells and blasts. The aim of this study is therefore to search those major RAS components simultaneously in the leukemic blast cells taken from the bone marrow of patients with acute myeloid leukemia (AML). METHODS: Bone marrow aspiration materials were obtained from 10 patients with AML (8 males, 2 females; median age 48.5 years) and 8 patients with nonmalignant hematological disorders (6 males, 2 females; median age 45 years). EDTA-treated bone marrow samples were stored at -70 degrees C until analysis. Total RNA was extracted from 200-microl bone marrow samples by High Pure RNA Isolation Kit. RESULTS: The medians of expression ratios of AML patient samples have been found 0.736 (IQR 1.359), 0.540 (IQR 0.725), and 0.075 (IQR 0.002) for ACE, ANG and REN genes, respectively. All three gene expressions were found to be significantly higher in the bone marrow samples of AML patients. CONCLUSION: In this study, the expression of the mRNAs of the major RAS components-namely ACE, renin and angiotensinogen-in human bone marrow samples were quantified by reverse transcription-polymerase chain reaction (RT-PCR) to confirm the presence of the local bone marrow RAS. Elucidation of the pathological activity of the local RAS-mediated regulation of the leukemogenesis is both pathobiologically and clinically important, since the angiotensin peptides represent a molecular target in the disease management.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abali Hüseyin, Güllü Ibrahim H., Engin Hüseyin, Haznedaroğlu Ibrahim C., Erman Mustafa, Tekuzman Gülten. Old antihypertensives as novel antineoplastics: angiotensin-I-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists. Med Hypotheses. 2002 Sep;59(3):344–348. doi: 10.1016/s0306-9877(02)00185-8. [DOI] [PubMed] [Google Scholar]
  2. Abali Hüseyin, Haznedaroglu Ibrahim C., Goker Hakan, Celik Ismail, Ozatli Düzgün, Koray Zehra, Caglar Meltem. Circulating and local bone marrow renin-angiotensin system in leukemic hematopoiesis: preliminary evidences. Hematology. 2002 Apr;7(2):75–82. doi: 10.1080/10245330290022160. [DOI] [PubMed] [Google Scholar]
  3. Bonnet D., Césaire R., Lemoine F., Aoudjhane M., Najman A., Guigon M. The tetrapeptide AcSDKP, an inhibitor of the cell-cycle status for normal human hematopoietic progenitors, has no effect on leukemic cells. Exp Hematol. 1992 Feb;20(2):251–255. [PubMed] [Google Scholar]
  4. Boranić M. While waiting for Christopher Columbus to discover alternative route(s) of bone marrow regulation, keep faith the body is a global system. Exp Hematol. 1998 Oct;26(11):1018–1019. [PubMed] [Google Scholar]
  5. Brunet de la Grange Philippe, Ivanovic Zoran, Leprivey-Lorgeot Valérie, Praloran Vincent. Angiotensin II that reduces the colony-forming ability of hematopoietic progenitors in serum free medium has an inverse effect in serum-supplemented medium. Stem Cells. 2002;20(3):269–271. doi: 10.1634/stemcells.20-3-269. [DOI] [PubMed] [Google Scholar]
  6. Caires Antonio C. F., Oliveira Carlos R., Smith Mickaela C. M., Hemerly Jefferson P., Juliano Maria A., Bincoletto Claudia. Effects of palladacycle complex on hematopoietic progenitor cells proliferation in vivo and in vitro and its relation with the inhibitory properties of this compound on the angiotensin-I converting enzyme activity. Immunopharmacol Immunotoxicol. 2004;26(4):487–500. doi: 10.1081/iph-200042263. [DOI] [PubMed] [Google Scholar]
  7. Charrier Sabine, Michaud Annie, Badaoui Sabrina, Giroux Sébastien, Ezan Eric, Sainteny Françoise, Corvol Pierre, Vainchenker William. Inhibition of angiotensin I-converting enzyme induces radioprotection by preserving murine hematopoietic short-term reconstituting cells. Blood. 2004 Apr 22;104(4):978–985. doi: 10.1182/blood-2003-11-3828. [DOI] [PubMed] [Google Scholar]
  8. Chisi J. E., Briscoe C. V., Ezan E., Genet R., Riches A. C., Wdzieczak-Bakala J. Captopril inhibits in vitro and in vivo the proliferation of primitive haematopoietic cells induced into cell cycle by cytotoxic drug administration or irradiation but has no effect on myeloid leukaemia cell proliferation. Br J Haematol. 2000 Jun;109(3):563–570. doi: 10.1046/j.1365-2141.2000.02073.x. [DOI] [PubMed] [Google Scholar]
  9. Chisi J. E., Wdzieczak-Bakala J., Thierry J., Briscoe C. V., Riches A. C. Captopril inhibits the proliferation of hematopoietic stem and progenitor cells in murine long-term bone marrow cultures. Stem Cells. 1999;17(6):339–344. doi: 10.1002/stem.170339. [DOI] [PubMed] [Google Scholar]
  10. Cobankara Veli, Oztürk Mehmet Akif, Kiraz Sedat, Ertenli Ihsan, Haznedaroglu Ibrahim C., Pay Salih, Calgüneri Meral. Renin and angiotensin-converting enzyme (ACE) as active components of the local synovial renin-angiotensin system in rheumatoid arthritis. Rheumatol Int. 2005 Mar 11;25(4):285–291. doi: 10.1007/s00296-004-0564-8. [DOI] [PubMed] [Google Scholar]
  11. Comte L., Lorgeot V., Bignon J., Volkov L., Dupuis F., Wdzieczak-Bakala J., Praloran V. In vivo modifications of AcSDKP metabolism and haematopoiesis in mice treated with 5-fluorouracil and Goralatide. Eur J Clin Invest. 1998 Oct;28(10):856–863. doi: 10.1046/j.1365-2362.1998.00356.x. [DOI] [PubMed] [Google Scholar]
  12. Danilov Sergei M., Sadovnikova Elena, Scharenborg Nicole, Balyasnikova Irina V., Svinareva Daria A., Semikina Elena L., Parovichnikova Elena N., Savchenko Valery G., Adema Gosse J. Angiotensin-converting enzyme (CD143) is abundantly expressed by dendritic cells and discriminates human monocyte-derived dendritic cells from acute myeloid leukemia-derived dendritic cells. Exp Hematol. 2003 Dec;31(12):1301–1309. doi: 10.1016/j.exphem.2003.08.018. [DOI] [PubMed] [Google Scholar]
  13. Defard M., Lemoine F. M., Bonnet M. L., Baillou C., Isnard F., Najman A., Guigon M. Comparison of the effects of AcSDKP, thymosin beta4, macrophage inflammatory protein 1alpha and transforming growth factor beta on human leukemic cells. Leuk Lymphoma. 1997 Nov;27(5-6):487–494. doi: 10.3109/10428199709058315. [DOI] [PubMed] [Google Scholar]
  14. Ellefson Dolph D., diZerega Gere S., Espinoza Theresa, Roda Norma, Maldonado Sonia, Rodgers Kathleen E. Synergistic effects of co-administration of angiotensin 1-7 and Neupogen on hematopoietic recovery in mice. Cancer Chemother Pharmacol. 2003 Oct 16;53(1):15–24. doi: 10.1007/s00280-003-0710-0. [DOI] [PubMed] [Google Scholar]
  15. Goker Hakan, Haznedaroglu Ibrahim C., Beyazit Yavuz, Aksu Salih, Tuncer Serdar, Misirlioglu Muge, Bayramoglu Fatma, Kekilli Murat, Büyükasik Yahya, Sayinalp Nilgun. Local umbilical cord blood renin-angiotensin system. Ann Hematol. 2005 Jan 11;84(5):277–281. doi: 10.1007/s00277-004-0989-x. [DOI] [PubMed] [Google Scholar]
  16. Goulter Andrew B., Goddard Martin J., Allen Jennifer C., Clark Kenneth L. ACE2 gene expression is up-regulated in the human failing heart. BMC Med. 2004 May 19;2:19–19. doi: 10.1186/1741-7015-2-19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hajek Dobroslav, Tomiska Miroslav, Krahulcova Eva, Druckmuller Miloslav, Florianova Michaela, Izakovicova-Holla Lydie, Vacha Jiri. I/D ACE gene polymorphism in survival of leukemia patients -- hypothesis and pilot study. Med Hypotheses. 2003 Jul;61(1):80–85. doi: 10.1016/s0306-9877(03)00122-1. [DOI] [PubMed] [Google Scholar]
  18. Haznedaroglu I. C. A local renin--angiotensin system in the bone marrow: hypothesis and clues. Exp Hematol. 1999 Jan;27(1):186–187. doi: 10.1016/s0301-472x(98)00066-6. [DOI] [PubMed] [Google Scholar]
  19. Haznedaroglu Ibrahim C., Oztürk M. Akif. Towards the understanding of the local hematopoietic bone marrow renin-angiotensin system. Int J Biochem Cell Biol. 2003 Jun;35(6):867–880. doi: 10.1016/s1357-2725(02)00278-9. [DOI] [PubMed] [Google Scholar]
  20. Haznedaroglu Ibrahim C., Oztürk M. Akif. Towards the understanding of the local hematopoietic bone marrow renin-angiotensin system. Int J Biochem Cell Biol. 2003 Jun;35(6):867–880. doi: 10.1016/s1357-2725(02)00278-9. [DOI] [PubMed] [Google Scholar]
  21. Haznedaroğlu I. C. Angiotensin I-converting enzyme, blood groups, and a local marrow-specific renin-angiotensin system. Exp Hematol. 1997 Feb;25(2):93–93. [PubMed] [Google Scholar]
  22. Haznedaroğlu I. C., Arici M., Büyükaşik Y. A unifying hypothesis for the renin-angiotensin system and hematopoiesis: sticking the pieces together with the JAK-STAT pathway. Med Hypotheses. 2000 Jan;54(1):80–83. doi: 10.1054/mehy.1998.0830. [DOI] [PubMed] [Google Scholar]
  23. Haznedaroğlu I. C., Büyükaşik Y. Current evidence for the existence of a local renin-angiotensin system affecting physiological and pathological haemopoiesis in the bone marrow. Br J Haematol. 1997 Nov;99(2):471–471. [PubMed] [Google Scholar]
  24. Haznedaroğlu I. C. Postrenal transplant erythrocytosis, ACE inhibitors and a hypothetical local renin-angiotensin system in the bone marrow. Clin Nephrol. 1997 Jul;48(1):60–60. [PubMed] [Google Scholar]
  25. Haznedaroğlu I. C., Tuncer S., Gürsoy M. A local renin-angiotensin system in the bone marrow. Med Hypotheses. 1996 Jun;46(6):507–510. doi: 10.1016/s0306-9877(96)90122-x. [DOI] [PubMed] [Google Scholar]
  26. Leung Po Sing. The peptide hormone angiotensin II: its new functions in tissues and organs. Curr Protein Pept Sci. 2004 Aug;5(4):267–273. doi: 10.2174/1389203043379693. [DOI] [PubMed] [Google Scholar]
  27. Liozon E., Pradelles P., Venot J., Rigaud M., Cransac M., Bordessoule D., Frindel E. Serum levels of a negative regulator of cell proliferation (AcSDKP) are increased in certain human haemopathies. Leukemia. 1993 Jun;7(6):808–812. [PubMed] [Google Scholar]
  28. Liozon E., Volkov L., Comte L., Trimoreau F., Pradelles P., Bordessoule D., Frindel E., Praloran V. AcSDKP serum concentrations vary during chemotherapy in patients with acute myeloid leukaemia. Br J Haematol. 1995 Apr;89(4):917–920. doi: 10.1111/j.1365-2141.1995.tb08438.x. [DOI] [PubMed] [Google Scholar]
  29. Marusic-Vrsalovic Maruska, Dominis Mara, Jaksic Branimir, Kusec Rajko. Angiotensin I-converting enzyme is expressed by erythropoietic cells of normal and myeloproliferative bone marrow. Br J Haematol. 2003 Nov;123(3):539–541. doi: 10.1046/j.1365-2141.2003.04598.x. [DOI] [PubMed] [Google Scholar]
  30. Nobuhiko Ayabe, Suganuma Eisuke, Babaev Vladimir R., Fogo Agnes, Swift Larry L., Linton MacRae F., Fazio Sergio, Ichikawa Iekuni, Kon Valentina. Angiotensin II amplifies macrophage-driven atherosclerosis. Arterioscler Thromb Vasc Biol. 2004 Sep 16;24(11):2143–2148. doi: 10.1161/01.ATV.0000145607.03879.e0. [DOI] [PubMed] [Google Scholar]
  31. Oztürk M. Akif, Güven Gülay Sain, Haznedaroglu Ibrahim C. How hematopoietic stem cells know and act in cardiac microenvironment for stem cell plasticity? Impact of local renin-angiotensin systems. Med Hypotheses. 2004;63(5):866–874. doi: 10.1016/j.mehy.2004.04.011. [DOI] [PubMed] [Google Scholar]
  32. Peng Cheng, Li Wei-Min, Ma Yan-Ping, Hu Zhong-Bo, Cheng Fan-Jun, Liu Ling-Bo, Zou Ping. [Effect of angiotensin II on cord blood CD34(+) cells expansion in vitro]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2003 Jun;11(3):227–229. [PubMed] [Google Scholar]
  33. Richmond Renee S., Tallant E. Ann, Gallagher Patricia E., Ferrario Carlos M., Strawn William B. Angiotensin II stimulates arachidonic acid release from bone marrow stromal cells. J Renin Angiotensin Aldosterone Syst. 2004 Dec;5(4):176–182. doi: 10.3317/jraas.2004.037. [DOI] [PubMed] [Google Scholar]
  34. Rodgers K. E., Xiong S., Steer R., diZerega G. S. Effect of angiotensin II on hematopoietic progenitor cell proliferation. Stem Cells. 2000;18(4):287–294. doi: 10.1634/stemcells.18-4-287. [DOI] [PubMed] [Google Scholar]
  35. Rodgers K. E., Xiong S., Steer R., diZerega G. S. Effect of angiotensin II on hematopoietic progenitor cell proliferation. Stem Cells. 2000;18(4):287–294. doi: 10.1634/stemcells.18-4-287. [DOI] [PubMed] [Google Scholar]
  36. Rodgers Kathleen E., Xiong Shiquin, diZerega Gere S. Accelerated recovery from irradiation injury by angiotensin peptides. Cancer Chemother Pharmacol. 2002 Mar 7;49(5):403–411. doi: 10.1007/s00280-002-0434-6. [DOI] [PubMed] [Google Scholar]
  37. Strawn William B., Richmond Renee S., Ann Tallant E., Gallagher Patricia E., Ferrario Carlos M. Renin-angiotensin system expression in rat bone marrow haematopoietic and stromal cells. Br J Haematol. 2004 Jul;126(1):120–126. doi: 10.1111/j.1365-2141.2004.04998.x. [DOI] [PubMed] [Google Scholar]
  38. Teresa Gomez Casares M., de la Iglesia Silvia, Perera Maria, Lemes Angelina, Campo Conrado, Gonzalez San Miguel Jose D., Bosch Jose M., Suarez Alexia, Guerra Luisa, Rodriguez-Peréz Jose C. Renin expression in hematological malignancies and its role in the regulation of hematopoiesis. Leuk Lymphoma. 2002 Dec;43(12):2377–2381. doi: 10.1080/1042819021000040080. [DOI] [PubMed] [Google Scholar]
  39. Vasku A., Hollá L., Znojil V. The best model of a cat is a cat, especially the same cat. Exp Hematol. 1999 Jan;27(1):187–188. doi: 10.1016/s0301-472x(98)00065-4. [DOI] [PubMed] [Google Scholar]
  40. Wierenga P. K., Konings A. W. Goralatide (AcSDKP) selectively protects murine hematopoietic progenitors and stem cells against hyperthermic damage. Exp Hematol. 1996 Feb;24(2):246–252. [PubMed] [Google Scholar]
  41. Wierenga P. K., Setroikromo R., Vellenga E., Kampinga H. H. Purging of acute myeloid leukaemia cells from stem cell grafts by hyperthermia: enhancement of the therapeutic index by the tetrapeptide AcSDKP and the alkyl-lysophospholipid ET-18-OCH(3). Br J Haematol. 2000 Dec;111(4):1145–1152. doi: 10.1046/j.1365-2141.2000.02469.x. [DOI] [PubMed] [Google Scholar]
  42. Wulf G. G., Jahns-Streubel G., Nobiling R., Strutz F., Hemmerlein B., Hiddemann W., Wörmann B. Renin in acute myeloid leukaemia blasts. Br J Haematol. 1998 Feb;100(2):335–337. doi: 10.1046/j.1365-2141.1998.00565.x. [DOI] [PubMed] [Google Scholar]
  43. Wulf G. G., Jahns-Streubel G., Strutz F., Basenau D., Hüfner M., Buske C., Wörmann B., Hiddemann W. Paraneoplastic hypokalemia in acute myeloid leukemia: a case of renin activity in AML blast cells. Ann Hematol. 1996 Sep;73(3):139–141. doi: 10.1007/s002770050215. [DOI] [PubMed] [Google Scholar]

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