Imatinib and Nilotinib Inhibit Hematopoietic Progenitor Cell Growth, but Do Not Prevent Adhesion, Migration and Engraftment of Human Cord Blood CD34+ Cells
[en] Background: The availability of tyrosine kinase inhibitors (TKIs) has considerably changed the management of Philadelphia chromosome positive leukemia. The BCR-ABL inhibitor imatinib is also known to inhibit the tyrosine kinase of the stem cell factor receptor, c-Kit. Nilotinib is 30 times more potent than imatinib towards BCR-ABL in vitro. Studies in healthy volunteers and patients with chronic myelogenous leukemia or gastrointestinal stromal tumors have shown that therapeutic doses of nilotinib deliver drug levels similar to those of imatinib. The aim of this study was to compare the inhibitory effects of imatinib and nilotinib on proliferation, differentiation, adhesion, migration and engraftment capacities of human cord blood CD34+ cells. Design and Methods: After a 48-hour cell culture with or without TKIs, CFC, LTC-IC, migration, adhesion and cell cycle analysis were performed. In a second time, the impact of these TKIs on engraftment was assessed in a xenotransplantation model using NOD/SCID/IL-2Rc (null) mice.
<br />Results: TKIs did not affect LTC-IC frequencies despite in vitro inhibition of CFC formation due to inhibition of CD34+ cell cycle entry. Adhesion of CD34+ cells to retronectin was reduced in the presence of either imatinib or nilotinib but only at high concentrations. Migration through a SDF-1a gradient was not changed by cell culture in the presence of TKIs. Finally, bone marrow cellularity and human chimerism were not affected by daily doses of imatinib and nilotinib in a xenogenic transplantation model. No significant difference was seen between TKIs given the equivalent affinity of imatinib and nilotinib for KIT.
<br />Conclusions: These data suggest that combining non-myeloablative conditioning regimen with TKIs starting the day of the transplantation could be safe.
Research Center/Unit :
GIGA-I3 - Giga-Infection, Immunity and Inflammation - ULiège
Imatinib and Nilotinib Inhibit Hematopoietic Progenitor Cell Growth, but Do Not Prevent Adhesion, Migration and Engraftment of Human Cord Blood CD34+ Cells
Publication date :
2012
Journal title :
PLoS ONE
eISSN :
1932-6203
Publisher :
Public Library of Science, San Franscisco, United States - California
Kurzrock R, Kantarjian HM, Druker BJ, Talpaz M, (2003) Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 138: 819-830.
Druker BJ, Lydon NB, (2000) Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 105: 3-7.
Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, et al. (2000) Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96: 925-932.
Mauro MJ, O'Dwyer M, Heinrich MC, Druker BJ, (2002) STI571: a paradigm of new agents for cancer therapeutics. J Clin Oncol 20: 325-334.
Manley PW, Stiefl N, Cowan-Jacob SW, Kaufman S, Mestan J, et al. (2010) Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib. Bioorg Med Chem 18: 6977-6986.
Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, et al. (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7: 129-141.
Weisberg E, Catley L, Wright RD, Moreno D, Banerji L, et al. (2007) Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias. Blood 109: 2112-2120.
Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, et al. (2006) AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer 94: 1765-1769.
von Bubnoff N, Manley PW, Mestan J, Sanger J, Peschel C, et al. (2006) Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107). Blood 108: 1328-1333.
Mohty M, Labopin M, Tabrizzi R, Theorin N, Fauser AA, et al. (2008) Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation. Haematologica 93: 303-306.
Baron F, Sandmaier BM, (2005) Current status of hematopoietic stem cell transplantation after nonmyeloablative conditioning. Curr Opin Hematol 12: 435-443.
Ram R, Storb R, Sandmaier BM, Maloney DG, Woolfrey A, et al. (2011) Non-myeloablative conditioning with allogeneic hematopoietic cell transplantation for the treatment of high-risk acute lymphoblastic leukemia. Haematologica 96: 1113-1120.
Yee NS, Paek I, Besmer P, (1994) Role of kit-ligand in proliferation and suppression of apoptosis in mast cells: basis for radiosensitivity of white spotting and steel mutant mice. J Exp Med 179: 1777-1787.
Haylock DN, To LB, Dowse TL, Juttner CA, Simmons PJ, (1992) Ex vivo expansion and maturation of peripheral blood CD34+ cells into the myeloid lineage. Blood 80: 1405-1412.
Miller CL, Rebel VI, Helgason CD, Lansdorp PM, Eaves CJ, (1997) Impaired steel factor responsiveness differentially affects the detection and long-term maintenance of fetal liver hematopoietic stem cells in vivo. Blood 89: 1214-1223.
Levesque JP, Leavesley DI, Niutta S, Vadas M, Simmons PJ, (1995) Cytokines increase human hemopoietic cell adhesiveness by activation of very late antigen (VLA)-4 and VLA-5 integrins. J Exp Med 181: 1805-1815.
Kim CH, Broxmeyer HE, (1998) In vitro behavior of hematopoietic progenitor cells under the influence of chemoattractants: stromal cell-derived factor-1, steel factor, and the bone marrow environment. Blood 91: 100-110.
Pirson L, Baron F, Meuris N, Giet O, Castermans E, et al. (2006) Despite inhibition of hematopoietic progenitor cell growth in vitro, the tyrosine kinase inhibitor imatinib does not impair engraftment of human CD133+ cells into NOD/SCIDbeta2mNull mice. Stem Cells 24: 1814-1821.
Vermeulen M, Le PF, Gagnerault MC, Mary JY, Sainteny F, et al. (1998) Role of adhesion molecules in the homing and mobilization of murine hematopoietic stem and progenitor cells. Blood 92: 894-900.
Peled A, Petit I, Kollet O, Magid M, Ponomaryov T, et al. (1999) Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 283: 845-848.
Lee SJ, Kukreja M, Wang T, Giralt SA, Szer J, et al. (2008) Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia. Blood 112: 3500-3507.
Jabbour E, Cortes J, Kantarjian H, Giralt S, Andersson BS, et al. (2007) Novel tyrosine kinase inhibitor therapy before allogeneic stem cell transplantation in patients with chronic myeloid leukemia: no evidence for increased transplant-related toxicity. Cancer 110: 340-344.
Breccia M, Palandri F, Iori AP, Colaci E, Latagliata R, et al. (2010) Second-generation tyrosine kinase inhibitors before allogeneic stem cell transplantation in patients with chronic myeloid leukemia resistant to imatinib. Leuk Res 34: 143-147.
Carpenter PA, Snyder DS, Flowers ME, Sanders JE, Gooley TA, et al. (2007) Prophylactic administration of imatinib after hematopoietic cell transplantation for high-risk Philadelphia chromosome-positive leukemia. Blood 109: 2791-2793.
Holtz MS, Slovak ML, Zhang F, Sawyers CL, Forman SJ, et al. (2002) Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood 99: 3792-3800.
Brendel C, Scharenberg C, Dohse M, Robey RW, Bates SE, et al. (2007) Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells. Leukemia 21: 1267-1275.
Bartolovic K, Balabanov S, Hartmann U, Komor M, Boehmler AM, et al. (2004) Inhibitory effect of imatinib on normal progenitor cells in vitro. Blood 103: 523-529.
O'Sullivan S, Lin JM, Watson M, Callon K, Tong PC, et al. (2011) The skeletal effects of the tyrosine kinase inhibitor nilotinib. Bone 49: 281-289.
Rosti V, Bergamaschi G, Lucotti C, Danova M, Carlo-Stella C, et al. (1995) Oligodeoxynucleotides antisense to c-abl specifically inhibit entry into S-phase of CD34+ hematopoietic cells and their differentiation to granulocyte-macrophage progenitors. Blood 86: 3387-3393.
Jorgensen HG, Allan EK, Jordanides NE, Mountford JC, Holyoake TL, (2007) Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood 109: 4016-4019.
Holyoake TL, Nicolini FE, Eaves CJ, (1999) Functional differences between transplantable human hematopoietic stem cells from fetal liver, cord blood, and adult marrow. Exp Hematol 27: 1418-1427.
Gigant C, Latger-Cannard V, Bensoussan D, Feugier P, Bordigoni P, et al. (2001) Quantitative expression of adhesion molecules on granulocyte colony-stimulating factor-mobilized peripheral blood, bone marrow, and cord blood CD34+ cells. J Hematother Stem Cell Res 10: 807-814.
Zheng YZ, Zhang L, Wang HJ, Han ZC, Takahashi TA, (2004) [Differential expression of a homing-related molecule repertoire among umbilical cord blood, mobilized peripheral blood and bone marrow-derived hematopoietic stem/progenitor cells]. Zhonghua Xue Ye Xue Za Zhi 25: 736-739.
Huygen S, Giet O, Artisien V, Di S, I, Beguin Y, et al. (2002) Adhesion of synchronized human hematopoietic progenitor cells to fibronectin and vascular cell adhesion molecule-1 fluctuates reversibly during cell cycle transit in ex vivo culture. Blood 100: 2744-2752.
Yong KL, Fahey A, Pizzey A, Linch DC, (2002) Influence of cell cycling and cell division on transendothelial migration of CD34+ cells. Br J Haematol 119: 500-509.
Levesque JP, Simmons PJ, (1999) Cytoskeleton and integrin-mediated adhesion signaling in human CD34+ hemopoietic progenitor cells. Exp Hematol 27: 579-586.
Hoepfl J, Miething C, Grundler R, Gotze KS, Peschel C, et al. (2002) Effects of imatinib on bone marrow engraftment in syngeneic mice. Leukemia 16: 1584-1588.
