Modification of gene expression in mesenchymal stromal cells of the acute myeloid leukemia patients during chemotherapy
T. V. Sorokina,
I. N. Shipunova,
A. E. Bigildeev,
N. I. Drize,
L. A. Kuzmina,
E. N. Parovichnikova,
V. G. Savchenko https://doi.org/10.18821/0234-5730/2016-61-3-126-133
Abstract
Aim of the study. To investigate the relevant expression level in multipotent mesenchymal stromal cells (MMCs) derived from the bone marrow (BM) of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients before and over the course of chemotherapy.
Material and Methods. BM derived MMSCs from 33 AML patients and 21 ALL patients were studied before and during chemotherapy. Total RNA was extracted from the MMSCs and the cDNA was synthesized. Gene expression levels were quantified by real-time quantitative PCR (RT-qPCR) with the use of gene-specific primers.
Results. Before chemotherapy, the analysis of the gene expression of MMSCs from acute leukemia patients revealed a significant increase in the relative expression level (REL) of genes (IL-6, IL-8, IL-1b, CSF, JAG1, ICAM, VCAM) which regulate leukemic cell proliferation and migration. The REL of genes regulating MMSC proliferation and differentiation (IL-1R1, PDGERa, IGF, FGFR1, FGFR2, BGLAP) increased during chemotherapy. The alterations of bone marrow stroma were more pronounced in patients who didn’t achieve remission.
Keywords
Supporting agencies: Russian Foundation of Basic Research, the Grant No 12-04-00457
About the Authors
T. V. Sorokina
National Research Center for Hematology
Russian Federation
Russian Federation
Sorokina Tamara V., MD, Doctor of the Department of High-Dose Chemotherapy, Depressions of Hemopoiesis, and Bone Marrow Transplantation
Moscow, 125167
I. N. Shipunova
National Research Center for Hematology
Russian Federation
125167, Moscow
Russian Federation
125167, Moscow
A. E. Bigildeev
National Research Center for Hematology
Russian Federation
125167, Moscow
Russian Federation
125167, Moscow
N. I. Drize
National Research Center for Hematology
Russian Federation
125167, Moscow
Russian Federation
125167, Moscow
L. A. Kuzmina
National Research Center for Hematology
Russian Federation
125167, Moscow
Russian Federation
125167, Moscow
E. N. Parovichnikova
National Research Center for Hematology
Russian Federation
125167, Moscow
Russian Federation
125167, Moscow
V. G. Savchenko
National Research Center for Hematology
Russian Federation
125167, Moscow
Russian Federation
125167, Moscow
References
1. Krampera M., Pizzolo G., Aprili G., Franchini M. Mesenchymal stem cells for bone, cartilage, tendon and skeletal muscle repair. Bone. 2006; 39(4): 678–83.
2. Caplan A. Mesenchymal stem cells. J. Orthop. Res. 1991; 9(5): 641–50.
3. Méndez-Ferrer S., Michurina T.V., Ferraro F., Mazloom A.R., MacArthur B.D., Lira S.A., et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010; 466(7308): 829–34.
4. Bruns I., Cadeddu R.P., Brueckmann I., Frobel J., Geyh S., Bust S., et al. Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells. Blood. 2012; 120(13) : 2620–30.
5. Suragani R.N., Cadena S.M., Cawley S.M., 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(4): 408–14. doi: 10.1038/nm.3512.
6. Chertkov J.L., Gurevitch O.A., Udalov G.A. Role of bone marrow stroma in hemopoietic stem cell regulation. Exp. Hematol. 1980; 8(6): 770–8.
7. Eppert K., Takenaka K., Lechman E.R., Waldron L., Nilsson B., van Galen P., et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat. Med. 2011; 17(9): 1086–93.
8. Gentles A.J., Plevritis S.K., Majeti R., Alizadeh A.A. Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia. JAMA. 2010; 304(24): 2706–15.
9. Fiedler W., Graeven U., Ergün S., Verago S., Kilic N., Stockschlader M., et al. Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia. Blood. 1997; 89(6): 1870–5.
10. Aguayo A., Estey E., Kantarjian H., Mansouri T., Gidel C., Keating M., et al. Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia. Blood. 1999; 94(11): 3717–21.
11. Loges S., Heil G., Bruweleit M., Schoder V., Butzal M., Fischer U., et al. Analysis of concerted expression of angiogenic growth factors in acute myeloid leukemia: expression of angiopoietin-2 represents an independent prognostic factor for overall survival. J. Clin. Oncol. 2005; 23(6): 1109–17.
12. Perez-Atayde A.R., Sallan S.E., Tedrow U., Connors S., Allred E., Folkman J. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am. J. Pathol. 1997; 150(3): 815–21.
13. Mirshahi P., Rafii A., Vincent L., Berthaut A., Varin R., Kalantar G., et al. Vasculogenic mimicry of acute leukemic bone marrow stromal cells. Leukemia.2009; 23(6): 1039–48.
14. Colmone A., Amorim M., Pontier A.L., Wang S., Jablonski E., Sipkins D.A. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science.2008; 322(5909): 1861–5.
15. Corre J., Mahtouk K., Attal M., Gadelorge M., Huynh A. FleuryCappellesso S., et al. Bone marrow mesenchymal stem cells are abnormal in multiple myeloma. Leukemia. 2007; 21(5): 1079–88.
16. Roela R.A., Carraro D.M., Brentani H.P., Kaiano J.H., Simao D.F., Guarnieiro R., et al. Gene stage-specific expression in the microenvironment of pediatric myelodysplastic syndromes. Leuk. Res. 2007; 31(5): 579–89.
17. Frisch B.J., Ashton J.M., Xing L., Becker M.W., Jordan C.T., Calvi L.M. Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemia. Blood. 2012; 119(2): 540–50. doi: 10.1182/blood-2011-04-348151.
18. Krevvata M., Silva B.C., Manavalan J.S., Galan-Diez M., Kode A., Matthews B.G., et al. Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts. Blood. 2014; 124(18): 2834–46.
19. Geyh S., Rodríguez-Paredes M., Jager P., Khandanpour C., Cadeddu R.P., Gutekunst J., et al. Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia. Leukemia. 2016; 30(3): 683–91.
20. Hanoun M., Zhang D., Mizoguchi T., Pinho S., Pierce H., Kunisaki Y., et al. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell. 2014; 15(3): 365–75.
21. Huan J., Hornick N.I., Shurtleff M.J., Skinner A.M., Goloviznina N.A., Roberts C.T., et al. RNA trafficking by acute myelogenous leukemia exosomes.Cancer Res. 2013; 73(2): 918–29.
22. Calkoen F.G., Vervat C., Eising E., Vijfhuizen L.S., ’t Hoen P.B., van den Heuvel-Eibrink M.M., et al. Gene-expression and in vitro function of mesenchymal stromal cells are affected in juvenile myelomonocytic leukemia. Haematologica. 2015; 100(11): 1434–41. doi: 10.3324/haematol.2015.126938.
23. Mudry R.E., Fortney J.E., York T., Hall B.M., Gibson L.F. Stromal cells regulate survival of B-lineage leukemic cells during chemotherapy. Blood. 2000; 96(5): 1926–32.
24. Ayala F., Dewar R., Kieran M., Kalluri R. Contribution of bone microenvironment to leukemogenesis and leukemia progression. Leukemia. 2009; 23(12): 2233–41.
25. Blau O. Bone marrow stromal cells in the pathogenesis of acute myeloid leukemia. Front. Biosci. (Landmark Ed.)2014; 19: 171–80.
26. Konopleva M., Zhao S., Hu W., Jiang S., Snell V., Weidner D., et al. The anti-apoptotic genes Bcl-X(L) and Bcl-2 are over-expressed and contribute to chemoresistance of non-proliferating leukaemic CD34+ cells. Br. J. Haematol. 2002; 118(2): 521–34.
27. Konopleva M., Konoplev S., Hu W., Zaritskey A.Y., Afanasiev B.V., Andreeff M. Stromal cells prevent apoptosis of AML cells by upregulation of anti-apoptotic proteins. Leukemia. 2002; 16(9): 1713–24.
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For citations:
Sorokina T.V., Shipunova I.N., Bigildeev A.E., Drize N.I., Kuzmina L.A., Parovichnikova E.N., Savchenko V.G. Modification of gene expression in mesenchymal stromal cells of the acute myeloid leukemia patients during chemotherapy. Russian journal of hematology and transfusiology. 2016;61(3):126-133. (In Russ.) https://doi.org/10.18821/0234-5730/2016-61-3-126-133
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