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Bone marrow mesenchymal stromal cells affect the cell cycle arrest effect of genotoxic agents on acute lymphocytic leukemia cells via p21 down-regulation

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Abstract

The effect of bone marrow microenvironment on the cell cycle of acute lymphocytic leukemia (ALL) and the underlying mechanism has not been elucidated. In this study, we found that in normal condition, bone marrow mesenchymal stromal cells (BM-MSCs) had no significant effect on the cell cycle and apoptosis of ALL; in the condition when the cell cycle of ALL was blocked by genotoxic agents, BM-MSCs could increase the S-phase cell ratio and decrease the G2/M phase ratio of ALL. Besides, BM-MSCs could protect ALL cells from drug-induced apoptosis. Then, we proved that BM-MSCs affect the cell cycle arrest effect of genotoxic agents on ALL cells via p21 down-regulation. Moreover, our results indicated that activation of Wnt/β-catenin and Erk pathways might be involved in the BM-MSC-induced down-regulation of p21 in ALL cells. Targeting microenvironment-related signaling pathway may therefore be a potential novel approach for ALL therapy.

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Reference

  1. Pui CH, Robison LL, Look AT (2008) Acute lymphoblastic leukaemia. Lancet 371(9617):1030–1043

    Article  CAS  PubMed  Google Scholar 

  2. Fielding AK, Richards SM, Chopra R et al (2007) Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 109(3):944–950

    Article  CAS  PubMed  Google Scholar 

  3. Colmone A, Amorim M, Pontier AL, Wang S, Jablonski E, Sipkins DA (2008) Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science 322(5909):1861–1865

    Article  CAS  PubMed  Google Scholar 

  4. Tesfai Y, Ford J, Carter KW et al (2012) Interactions between acute lymphoblastic leukemia and bone marrow stromal cells influence response to therapy. Leuk Res 36(3):299–306

    Article  CAS  PubMed  Google Scholar 

  5. Parameswaran R, Yu M, Lyu MA et al (2012) Treatment of acute lymphoblastic leukemia with an rGel/BLyS fusion toxin. Leukemia 26(8):1786–1796

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Gaundar SS, Bradstock KF, Bendall LJ (2009) p38MAPK inhibitors attenuate cytokine production by bone marrow stromal cells and reduce stroma-mediated proliferation of acute lymphoblastic leukemia cells. Cell Cycle 8(18):2975–2983

    Article  PubMed  Google Scholar 

  7. Scupoli MT, Donadelli M, Cioffi F et al (2008) Bone marrow stromal cells and the upregulation of interleukin-8 production in human T-cell acute lymphoblastic leukemia through the CXCL12/CXCR4 axis and the NF-kappaB and JNK/AP-1 pathways. Haematologica 93(4):524–532

    Article  CAS  PubMed  Google Scholar 

  8. Juarez J, Dela Pena A, Baraz R et al (2007) CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment. Leukemia 21(6):1249–1257

    Article  CAS  PubMed  Google Scholar 

  9. Juarez J, Baraz R, Gaundar S, Bradstock K, Bendall L (2007) Interaction of interleukin-7 and interleukin-3 with the CXCL12-induced proliferation of B-cell progenitor acute lymphoblastic leukemia. Haematologica 92(4):450–459

    Article  CAS  PubMed  Google Scholar 

  10. O'Leary H, Akers SM, Piktel D et al (2010) VE-cadherin regulates Philadelphia chromosome positive acute lymphoblastic leukemia sensitivity to apoptosis. Cancer Microenviron 3(1):67–81

    Article  PubMed Central  PubMed  Google Scholar 

  11. Wang L, O'Leary H, Fortney J, Gibson LF (2007) Ph+/VE-cadherin + identifies a stem cell like population of acute lymphoblastic leukemia sustained by bone marrow niche cells. Blood 110(9):3334–3344

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Zhang X, Liu Y, Si YJ et al (2012) Effect of Cx43 gene-modified leukemic bone marrow stromal cells on the regulation of Jurkat cell line in vitro. Leuk Res 36(2):198–204

    Article  CAS  PubMed  Google Scholar 

  13. Nwabo Kamdje AH, Mosna F, Bifari F et al (2011) Notch-3 and Notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow-derived mesenchymal stromal cells. Blood 118(2):380–389

    Article  PubMed  Google Scholar 

  14. Yang Y, Mallampati S, Sun B et al (2013) Wnt pathway contributes to the protection by bone marrow stromal cells of acute lymphoblastic leukemia cells and is a potential therapeutic target. Cancer Lett 333:9–17

    Article  CAS  PubMed  Google Scholar 

  15. Silva A, Laranjeira AB, Martins LR et al (2011) IL-7 contributes to the progression of human T-cell acute lymphoblastic leukemias. Cancer Res 71(14):4780–4789

    Article  CAS  PubMed  Google Scholar 

  16. de Vasconcellos JF, Laranjeira AB, Zanchin NI et al (2011) Increased CCL2 and IL-8 in the bone marrow microenvironment in acute lymphoblastic leukemia. Pediatr Blood Cancer 56(4):568–577

    Article  PubMed  Google Scholar 

  17. Batista A, Barata JT, Raderschall E et al (2011) Targeting of active mTOR inhibits primary leukemia T cells and synergizes with cytotoxic drugs and signaling inhibitors. Exp Hematol 39(4):457–472 e453

    Article  CAS  PubMed  Google Scholar 

  18. Dosen-Dahl G, Munthe E, Nygren MK, Stubberud H, Hystad ME, Rian E (2008) Bone marrow stroma cells regulate TIEG1 expression in acute lymphoblastic leukemia cells: role of TGFbeta/BMP-6 and TIEG1 in chemotherapy escape. Int J Cancer 123(12):2759–2766

    Article  PubMed  Google Scholar 

  19. Markovic A, MacKenzie KL, Lock RB (2012) Induction of vascular endothelial growth factor secretion by childhood acute lymphoblastic leukemia cells via the FLT-3 signaling pathway. Mol Cancer Ther 11(1):183–193

    Article  CAS  PubMed  Google Scholar 

  20. Fragoso R, Pereira T, Wu Y, Zhu Z, Cabecadas J, Dias S (2006) VEGFR-1 (FLT-1) activation modulates acute lymphoblastic leukemia localization and survival within the bone marrow, determining the onset of extramedullary disease. Blood 107(4):1608–1616

    Article  CAS  PubMed  Google Scholar 

  21. Fung KL, Liang RH, Chan GC (2010) Vincristine but not imatinib could suppress mesenchymal niche's support to lymphoid leukemic cells. Leuk Lymphoma 51(3):515–522

    Article  CAS  PubMed  Google Scholar 

  22. Iwamoto S, Mihara K, Downing JR, Pui CH, Campana D (2007) Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase. J Clin Invest 117(4):1049–1057

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Frolova O, Samudio I, Benito JM et al (2012) Regulation of HIF-1alpha signaling and chemoresistance in acute lymphocytic leukemia under hypoxic conditions of the bone marrow microenvironment. Cancer Biol Ther 13(10):858–870

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Dong-Feng Z, Ting L, Cheng C et al (2012) Silencing HIF-1alpha reduces the adhesion and secretion functions of acute leukemia hBMSCs. Braz J Med Biol Res 45(10):906–912

    PubMed  Google Scholar 

  25. Benito J, Shi Y, Szymanska B et al (2011) Pronounced hypoxia in models of murine and human leukemia: high efficacy of hypoxia-activated prodrug PR-104. PLoS One 6(8):e23108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Hande KR (1998) Etoposide: four decades of development of a topoisomerase II inhibitor. Eur J Cancer 34(10):1514–1521

    Article  CAS  PubMed  Google Scholar 

  27. Zhu Y, Sun Z, Han Q et al (2009) Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia 23(5):925–933

    Article  CAS  PubMed  Google Scholar 

  28. Warfel NA, El-Deiry WS (2013) p21WAF1 and tumourigenesis: 20 years after. Curr Opin Oncol 25(1):52–58

    Article  CAS  PubMed  Google Scholar 

  29. Shiu TY, Huang SM, Shih YL, Chu HC, Chang WK, Hsieh TY (2013) Hepatitis C virus core protein down-regulates p21(Waf1/Cip1) and inhibits curcumin-induced apoptosis through microRNA-345 targeting in human hepatoma cells. PLoS One 8(4):e61089

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Ahmad N, Feyes DK, Agarwal R, Mukhtar H (1998) Photodynamic therapy results in induction of WAF1/CIP1/P21 leading to cell cycle arrest and apoptosis. Proc Natl Acad Sci U S A 95(12):6977–6982

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. el-Deiry WS, Tokino T, Velculescu VE et al (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75(4):817–825

    Article  CAS  PubMed  Google Scholar 

  32. Mitchell KO, El-Deiry WS (1999) Overexpression of c-Myc inhibits p21WAF1/CIP1 expression and induces S-phase entry in 12-O-tetradecanoylphorbol-13-acetate (TPA)-sensitive human cancer cells. Cell Growth Differ 10(4):223–230

    CAS  PubMed  Google Scholar 

  33. Bornstein G, Bloom J, Sitry-Shevah D, Nakayama K, Pagano M, Hershko A (2003) Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. J Biol Chem 278(28):25752–25757

    Article  CAS  PubMed  Google Scholar 

  34. Cornils H, Kohler RS, Hergovich A, Hemmings BA (2011) Human NDR kinases control G(1)/S cell cycle transition by directly regulating p21 stability. Mol Cell Biol 31(7):1382–1395

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Drexler HG, Quentmeier H, Dirks WG, Uphoff CC, MacLeod RA (2002) DNA profiling and cytogenetic analysis of cell line WSU-CLL reveal cross-contamination with cell line REH (pre B-ALL). Leukemia 16(9):1868–1870

    Article  CAS  PubMed  Google Scholar 

  36. Zhao YM, Li JY, Lan JP et al (2008) Cell cycle dependent telomere regulation by telomerase in human bone marrow mesenchymal stem cells. Biochem Biophys Res Commun 369(4):1114–1119

    Article  CAS  PubMed  Google Scholar 

  37. Tanaka T, Nakatani T, Kamitani T (2012) Inhibition of NEDD8-conjugation pathway by novel molecules: potential approaches to anticancer therapy. Mol Oncol 6(3):267–275

    Article  CAS  PubMed  Google Scholar 

  38. Chen H, Landen CN, Li Y, Alvarez RD, Tollefsbol TO (2013) Enhancement of cisplatin-mediated apoptosis in ovarian cancer cells through potentiating G2/M arrest and p21 upregulation by combinatorial epigallocatechin gallate and sulforaphane. J Oncol 2013:872957

    Article  PubMed Central  PubMed  Google Scholar 

  39. Vijayaraghavalu S, Dermawan JK, Cheriyath V, Labhasetwar V (2013) Highly synergistic effect of sequential treatment with epigenetic and anticancer drugs to overcome drug resistance in breast cancer cells is mediated via activation of p21 gene expression leading to G2/M cycle arrest. Mol Pharm 10(1):337–352

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Wu KN, Zhao YM, He Y et al (2014) Rapamycin interacts synergistically with idarubicin to induce T-leukemia cell apoptosis in vitro and in a mesenchymal stem cell simulated drug-resistant microenvironment via Akt/mammalian target of rapamycin and extracellular signal-related kinase signaling pathways. Leuk Lymphoma 55(3):668–676

    Article  CAS  PubMed  Google Scholar 

  41. Li Y, Gao Q, Yin G, Ding X, Hao J (2012) WNT/beta-catenin-signaling pathway stimulates the proliferation of cultured adult human Sertoli cells via upregulation of C-myc expression. Reprod Sci 19(11):1232–1240

    Article  PubMed  Google Scholar 

  42. Pintus G, Tadolini B, Posadino AM et al (2002) Inhibition of the MEK/ERK signaling pathway by the novel antimetastatic agent NAMI-A down regulates c-myc gene expression and endothelial cell proliferation. Eur J Biochem 269(23):5861–5870

    Article  CAS  PubMed  Google Scholar 

  43. Lanza F, Campioni D, Moretti S et al (2007) Aberrant expression of HLA-DR antigen by bone marrow-derived mesenchymal stromal cells from patients affected by acute lymphoproliferative disorders. Leukemia 21(2):378–381

    Article  CAS  PubMed  Google Scholar 

  44. Campioni D, Lanza F, Moretti S, Ferrari L, Cuneo A et al (2008) Loss of Thy-1 (CD90) antigen expression on mesenchymal stromal cells from hematologic malignancies is induced by in vitro angiogenic stimuli and is associated with peculiar functional and phenotypic characteristics. Cytotherapy 10(1):69–82

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from National High-tech R&D Program of China (863 Program, grant No. N20120221) and Zhejiang Provincial Natural Science Foundation of China (grant No. Y2110152).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

    Yiran Zhang, Kaimin Hu, Yongxian Hu, Lizhen Liu, Binsheng Wang & He Huang

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  1. Yiran Zhang
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  2. Kaimin Hu
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Correspondence to He Huang.

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Zhang, Y., Hu, K., Hu, Y. et al. Bone marrow mesenchymal stromal cells affect the cell cycle arrest effect of genotoxic agents on acute lymphocytic leukemia cells via p21 down-regulation. Ann Hematol 93, 1499–1508 (2014). https://doi.org/10.1007/s00277-014-2069-1

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  • DOI: https://doi.org/10.1007/s00277-014-2069-1

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