Gene expression profiles of CD34+ cells in myelodysplastic syndromes: involvement of interferon-stimulated genes and correlation to FAB subtype and karyotype.

To gain insight into the poorly understood pathophysiology of the myelodysplastic syndromes (MDSs), we have determined the gene expression profiles of the CD34+ cells of 55 patients with MDS by using a comprehensive array platform. These profiles showed many similarities to reported interferon-gamma-induced gene expression in normal CD34+ cells; indeed the 2 most up-regulated genes, IFIT1 and IFITM1, are interferon-stimulated genes (ISGs). Alterations in the expression of ISGs may play a role in the hematologic features of MDS, such as peripheral blood cytopenias. Up-regulation of IFIT1 is a potential diagnostic marker for MDS. We determined whether distinct gene expression profiles were associated with specific FAB and cytogenetic groups. CD34+ cells from patients with refractory anemia with ringed sideroblasts (RARS) showed a particular gene expression profile characterized by up-regulation of mitochondrial-related genes and, in particular, of those of heme synthesis (eg, ALAS2). CD34+ cells from patients with the del(5q) had a distinct gene expression profile, characterized by down-regulation of genes assigned to 5q, and up-regulation of the histone HIST1 gene cluster at chromosome 6p21 and of genes related to the actin cytoskeleton. This study provides important and new insights into the pathophysiology of MDS.

[1]  P. Vyas,et al.  Evidence for reduced B-cell progenitors in early (low-risk) myelodysplastic syndrome. , 2005, Blood.

[2]  M. L. Beau,et al.  The cytogenetics of myelodysplastic syndromes. , 2001, Best practice & research. Clinical haematology.

[3]  S. Kajigaya,et al.  Gene expression profiling in CD34 cells to identify differences between aplastic anemia patients and healthy volunteers. , 2004, Blood.

[4]  D. Caput,et al.  Expression Cloning of an Interferon-inducible 17-kDa Membrane Protein Implicated in the Control of Cell Growth (*) , 1995, The Journal of Biological Chemistry.

[5]  J. Boultwood,et al.  The 5q-syndrome. , 1994, Blood.

[6]  L. Larue,et al.  The WNT/Beta-catenin pathway in melanoma. , 2006, Frontiers in bioscience : a journal and virtual library.

[7]  H Phillip Koeffler,et al.  Myelodysplastic Bone Marrow Cells from Normal and + Characterization of Gene Expression of Cd34 , 2002 .

[8]  T. Pollard,et al.  Crystal Structure of Arp2/3 Complex , 2001, Science.

[9]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[10]  G. Tricot,et al.  The 5q-anomaly. , 1985, Cancer genetics and cytogenetics.

[11]  S. E. Jacobsen,et al.  IFN-γ Negatively Modulates Self-Renewal of Repopulating Human Hemopoietic Stem Cells1 , 2005, The Journal of Immunology.

[12]  P. Fenaux.  Chromosome and Molecular Abnormalities in Myelodysplastic Syndromes , 2001, International journal of hematology.

[13]  A. Verma,et al.  Cytokine targets in the treatment of myelodysplastic syndromes. , 2005, Current hematology reports.

[14]  L. Rimsza,et al.  Efficacy of lenalidomide in myelodysplastic syndromes. , 2005, The New England journal of medicine.

[15]  H. Preisler,et al.  Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes. , 1995, Blood.

[16]  E. Schuuring,et al.  Identification and cloning of two overexpressed genes, U21B31/PRAD1 and EMS1, within the amplified chromosome 11q13 region in human carcinomas. , 1992, Oncogene.

[17]  J U Gutterman,et al.  Cytokine therapeutics: lessons from interferon alpha. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[18]  B. Zhivotovsky,et al.  Granulocyte colony-stimulating factor inhibits spontaneous cytochrome c release and mitochondria-dependent apoptosis of myelodysplastic syndrome hematopoietic progenitors. , 2003, Blood.

[19]  D. Helfman,et al.  Cytoskeletal changes in cell transformation and tumorigenesis. , 2001, Current opinion in genetics & development.

[20]  R. Hoffman,et al.  Hematology: Basic Principles and Practice , 1995 .

[21]  C. Dai,et al.  Stem cell factor increases the expression of FLIP that inhibits IFNgamma -induced apoptosis in human erythroid progenitor cells. , 2003, Blood.

[22]  M. Cazzola,et al.  Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia. , 2003, Blood.

[23]  T. Naoe,et al.  Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. , 2004, Blood.

[24]  Y. Yamashita,et al.  Identification of myelodysplastic syndrome-specific genes by DNA microarray analysis with purified hematopoietic stem cell fraction. , 2001, Blood.

[25]  P. Tsoplou,et al.  Apoptosis in patients with myelodysplastic syndromes: differential involvement of marrow cells in ‘good’ versus ‘poor’ prognosis patients and correlation with apoptosis-related genes , 1999, Leukemia.

[26]  C. Schoch,et al.  Clinical, morphological, cytogenetic, and prognostic features of patients with myelodysplastic syndromes and del(5q) including band q31 , 2004, Leukemia.

[27]  T Hamblin,et al.  International scoring system for evaluating prognosis in myelodysplastic syndromes. , 1997, Blood.

[28]  G Flandrin,et al.  World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  M. Hubank.  Gene expression profiling and its application in studies of haematological malignancy , 2004, British journal of haematology.

[30]  D. Steensma,et al.  Genetic testing in the myelodysplastic syndromes: molecular insights into hematologic diversity. , 2005, Mayo Clinic proceedings.

[31]  C. Langford,et al.  Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the α-thalassemia myelodysplasia syndrome (ATMDS) , 2003, Nature Genetics.

[32]  R. Eils,et al.  Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[33]  S. Kajigaya,et al.  Interferon-gamma-induced gene expression in CD34 cells: identification of pathologic cytokine-specific signature profiles. , 2006, Blood.

[34]  R. Abramson,et al.  Detection of specific polymerase chain reaction product by utilizing the 5'----3' exonuclease activity of Thermus aquaticus DNA polymerase. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[35]  R. Tibshirani,et al.  Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. , 2004, The New England journal of medicine.

[36]  T. A. Lister,et al.  Genome‐wide analysis of acute myeloid leukemia with normal karyotype reveals a unique pattern of homeobox gene expression distinct from those with translocation‐mediated fusion events , 2003, Genes, chromosomes & cancer.

[37]  P. Ji,et al.  Alterations of lymphoid enhancer factor-1 isoform expression in solid tumors and acute leukemias. , 2005, Acta biochimica et biophysica Sinica.

[38]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[39]  N. Cross,et al.  Low expression of the putative tumour suppressor gene gravin in chronic myeloid leukaemia, myelodysplastic syndromes and acute myeloid leukaemia , 2004, British journal of haematology.

[40]  C. Langford,et al.  Gene expression profiling in polycythemia vera using cDNA microarray technology. , 2003, Cancer research.

[41]  K. Livak,et al.  Real time quantitative PCR. , 1996, Genome research.

[42]  D. Galton.  The myelodysplastic syndromes. , 1987, Clinical and laboratory haematology.

[43]  P. Greenberg,et al.  Altered oncoprotein expression and apoptosis in myelodysplastic syndrome marrow cells , 1996 .

[44]  Bengt Fadeel,et al.  Apoptosis in refractory anaemia with ringed sideroblasts is initiated at the stem cell level and associated with increased activation of caspases , 2001, British journal of haematology.

[45]  H. Gralnick,et al.  Proposals for the classification of the myelodysplastic syndromes , 1982, British journal of haematology.

[46]  C. Langford,et al.  Gene expression profiling in the myelodysplastic syndromes using cDNA microarray technology , 2004, British journal of haematology.

[47]  Y Yoshida,et al.  Pathogenesis, etiology and epidemiology of myelodysplastic syndromes. , 1998, Haematologica.

[48]  E. Sausville,et al.  dlk, a putative mammalian homeotic gene differentially expressed in small cell lung carcinoma and neuroendocrine tumor cell line. , 1993, The Journal of biological chemistry.

[49]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[50]  K. Hirokawa,et al.  Overexpression of tumor necrosis factor (TNF)-α and interferon (IFN)-γ by bone marrow cells from patients with myelodysplastic syndromes , 1997, Leukemia.

[51]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[52]  W. Hiddemann,et al.  Genomic gains and losses influence expression levels of genes located within the affected regions: a study on acute myeloid leukemias with trisomy 8, 11, or 13, monosomy 7, or deletion 5q , 2005, Leukemia.

[53]  J. D. Vos,et al.  Fas/Apo-1(CD95) expression and apoptosis in patients with myelodysplastic syndromes , 1997, Leukemia.