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Mobilisation with G-CSF in Healthy Donors Promotes a High but Temporal Deregulation of Genes

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Mobilisation with G-CSF in Healthy Donors Promotes a High but Temporal Deregulation of Genes Correspondence 1088 Mobilisation with G-CSF in healthy donors promotes a high but temporal deregulation of genes Leukemia (2005) 19, 1088–1091. doi:10.1038/sj.leu.2403753 version 3.0) and SAM algorithm (‘Significant Analysis of Published online 14 April 2005 Microarrays’). A two-dimensional hierarchical clustering analysis performed TO THE EDITOR on 9203 genes passing the variation filter showed a dendogram with two major branches: one branch included all the donors Over recent years, the use of peripheral blood (PB) instead of after mobilisation with G-CSF, while in the other branch, the bone marrow (BM) as a source for stem cells has been gene profiles from the donors before mobilisation and 2 and 6 increasingly employed both in the autologous and in the months after G-CSF administration were grouped (Figure 1). allogeneic transplant setting. The advantages of peripheral blood When multidimensional scaling analysis was performed, sam- stem cells (PBSC) include easier harvesting of stem cells, ples on day 0 and those on day þ 5 were also assigned into two avoidance of anaesthesia and hospitalisation as well as improved well-differentiated groups. yield of progenitor cells, and a more rapid and robust Genes distinguishing the day 0 samples from the day þ 5 engraftment. However, it should also be taken into account samples were identified as significant by the intersection of data that PBSC mobilisation requires the administration of haemato- sets from SAM analysis. A total of 761 genes distinguished the poietic cytokines (ie granulocyte colony-stimulating factor (G- two groups: 374 increased their expression level, while 387 CSF)) over several days, which stimulate proliferation and decreased their expression level after G-CSF (Table 1). Our differentiation of myeloid cell lineage.1 Extensive experience so initial design included a revaluation of the donors 6 months after far accumulated with G-CSF in patients being treated for mobilisation with G-CSF. Moreover, in order to better determine neutropenia as well as in patients undergoing autologous stem the timing of normal recovery, an additional analysis just 2 cell mobilisation indicates that it is a safe procedure. Never- months after G-CSF administration was also performed. No gene theless, the parameters used for the safety evaluation have been was found to be under- or overexpressed after comparing the rather crude and mainly focus on morphological and cytogenetic samples before G-CSF and 2 or 6 months after G-CSF. Moreover, changes in haemopoietic cells.2 Therefore, variations in other cell systems may have gone undetected. This is particularly relevant when considering the use of G-CSF in healthy volunteer individuals. Analysis of gene expression profiles (GEP) using microarray technology has become a powerful tool for studying the expression of the most important genes in a single experiment. As such, the possibility to study thousands of genes and their cellular functions in the same experiment by microarrays could provide powerful information.3 Despite the increasing use of PBSC transplantation, the changes induced by PBSC mobilisation and homing are not clear yet. To gain insight into the effects of G-CSF, used as PBSC mobilisation agent, the GEP of healthy donors was evaluated. In addition, in order to assess the duration of this effect, sequential studies on gene expression were also performed. PB samples from nine healthy donors were studied. All donors were mobilised by using G-CSF (Filgastrim, Amgen) at a dose of 5 mg/kg/q12 h for 4 days, and peripheral stem cells were collected on day þ 5. For genomic profile purposes, the samples were collected just before G-CSF administration, and after mobilisation (day þ 5) in all nine donors investigated. In addition, samples were also collected 2 and 6 months after mobilisation in three of these donors. The study was approved by the local research ethics committee and written informed consent was obtained. Venous PB (20 ml) were obtained from each donor. Mononuclear cells were isolated by Ficoll–Hypaque gradient centrifugation. Data analysis were performed by Hierarchical clustering (Cluster and TreeView software), Multidimensional scaling method (BRB Array Tools Correspondence: Dr JM Herna´ndez, Servicio de Hematologı´a, Figure 1 Dendogram from a hierarchical cluster analysis of the 24 Hospital Universitario de Salamanca, Paseo San Vicente 58-182, PB samples from healthy donors. Based on the expression of 9203 Salamanca 37007, Spain; Fax: þ 34 923 294624; genes passing a variation filter generated by using Cluster and E-mail: [email protected] TreeView programs. Horizontal bars along the dendogram represent Received 5 October 2004; accepted 4 March 2005; Published online samples 5 days after G-CSF (a) and samples before G-CSF as well as 2 14 April 2005 and 6 months after G-CSF (b). Leukemia Correspondence 1089 Table 1 Genes differentially expressed between mononuclear cells obtained before and after donor mobilisation with G-CSF (day +5) Gene symbol Name Representative public ID Score Signal transduction RAB13 RAB13, member RAS oncogene family NM_002870 3.95653 RAB27 RAB27, member RAS oncogene family BE502030 5.14411 RAB31 RAB31, member RAS oncogene family AF183421 3.68171 RAB32 RAB32, member RAS oncogene family NM_006834 3.47248 TGFBR3 Transforming growth factor, beta receptor III NM_003243 À4.68711 MAPK14 Mitogen-activated protein kinase 14 L35253 2.92736 MAP2K3 Mitogen-activated protein kinase kinase 3 NM_002756 2.52934 MAP2K6 Mitogen-activated protein kinase kinase 6 NM_002758 4.28510 ARF3 ADP-ribosylation factor 3 BG341906 3.36163 WAS Wiskott–Aldrich syndrome NM_000377 2.77877 RGS19 Regulator of G-protein signalling 19 NM_005873 2.53418 ZAP-70 Zeta-chain (TCR)-associated protein kinase 70 kDa AI817942 À3.24105 Regulation of transcription HMGB3 High-mobility group box 3 NM_005342 3.94948 TCF7L2 Transcription factor 7-like 2 (T-cell-specific, HMG box) AJ270770 3.05730 TFE3 Transcription factor binding to IGHM enhancer 3 NM_006521 3.07648 ETS2 V-ets erythroblastosis virus E26 oncogene homologue 2 (avian) AL575509 3.37649 DEDD Death effector domain containing AK022531 2.51070 DR1 Downregulator of transcription 1, TBP binding (negative cofactor 2) BC002809 3.30749 SPI1 Spleen focus-forming virus (SFFV) proviral integration oncogene spi1 NM_003120 3.74748 ENO1 Enolase 1, (alpha) NM_001428 2.75180 MAF V-maf musculoaponeurotic fibrosarcoma oncogene homologue (avian) NM_005360 À6.54406 POU2AF1 POU domain, class 2, associating factor 1 NM_006235 À2.58406 FOXO1A Forkhead box O1A (rhabdomyosarcoma) AW117498 À2.59546 LEF1 Lymphoid enhancer-binding factor 1 AF288571 À3.61586 TCF7 Transcription factor 7 (T-cell-specific, HMG box) NM_003202 À4.10923 TCF8 Transcription factor 8 (represses interleukin 2 expression) AI806174 À2.29037 TTF1 Transcription termination factor, Immune response AI632304 À2.35126 TCRa T-cell receptor alpha locus M15565 À5.67759 TCRg T-cell receptor gamma locus M16768 À3.13169 TCRd T-cell receptor delta locus AW007751 À4.06956 GATA3 GATA binding protein 3 BC003070 À5.13378 HLADMB Major histocompatibility complex, class II, DM beta NM_002118 À2.234549 HLADPb1 Major histocompatibility complex, class II, DP beta 1 NM_002121 À4.84826 HLADQa1 Major histocompatibility complex, class II, DQ alpha 1 BG397856 À5.25875 HLADRa Major histocompatibility complex, class II, DR alpha M60333 À3.97510 HLADPa1 Major histocompatibility complex, class II, DP alpha 1 M27487 À3.81689 HLADRb3 Major histocompatibility complex, class II, DR beta 3 U65585 À4.61260 CD2 CD2 antigen (p50), sheep red blood cell receptor NM_001767 À5.08437 CD3D CD3D antigen, delta polypeptide NM_000732 À4.55901 CD3G CD3G antigen, gamma polypeptide NM_000073 À4.87048 CD3Z CD3Z antigen, zeta polypeptide J04132 À3.31963 CD7 CD7 antigen NM_006137 À3.21026 CD6 CD6 antigen AW134823 À2.52963 CD8A CD8 antigen, alpha polypeptide AW006735 À4.00413 CD96 CD96 antigen NM_005816 À3.43420 CD14 CD14 antigen NM_000591 3.18541 CD24 CD24 antigen AA761181 9.80223 Cell adhesion ICAM2 Intercellular adhesion molecule 2 AA126728 À5.09797 CD11b Integrin, alpha M NM_000632 3.55695 MMP8 Matrix metalloproteinase 8 NM_002424 10.33851 MMP9 Matrix metalloproteinase 9 NM_004994 3.39373 ELA2 Elastase 2, neutrophil NM_001972 9.77109 CTSG Cathepsin G NM_001911 5.25725 PRNT3 Proteinase 3 NM_002777 11.03728 CDC42 CDC42 effector protein AI754416 4.00483 CEACAM1 Carcinoembryonic antigen-related cell adhesion molecule 1 NM_001712 2.95220 CEACAM4 Carcinoembryonic antigen-related cell adhesion molecule 4 NM_001817 3.35042 CEACAM6 Carcinoembryonic antigen-related cell adhesion molecule 6 BC005008 7.10602 CEACAM8 Carcinoembryonic antigen-related cell adhesion molecule 8 M33326 10.25315 CD44 CD44 antigen (homing function (and Indian blood group system) BC004372 2.95859 CD58 CD58 antigen (lymphocyte function associated) BC005930 2.38752 CD2 CD2 antigen (p50), sheep red blood cell receptor NM_001767 À5.08437 CD6 CD6 antigen AW134823 À2.52963 CD96 CD96 antigen NM_005816 À3.43420 CD99 CD99 antigen NM_002414 À2.92788 Leukemia Correspondence 1090 Table 1 (Continued ) Gene symbol Name Representative public ID Score Cell proliferation BTG1 B-cell translocation gene 1, antiproliferative AL535380 À2.98168 FGFR10 PFGFR1 oncogene partner NM_007045 2.54370 HDGF Hepatoma-derived growth factor L24521 2.71563 LRPAP1 Low-density lipoprotein receptor-related protein associated NM_002337 3.53960 IL2RG Interleukin 2 receptor, gamma NM_000206 2.57537 S100A11 S100 calcium binding protein A11 NM_005620 2.94190 S100A6 S100 calcium
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