Serum proteome profiling detects myelodysplastic syndromes and identifies CXC chemokine ligands 4 and 7 as markers for advanced disease

Myelodysplastic syndromes (MDS) are among the most frequent hematologic malignancies. Patients have a short survival and often progress to acute myeloid leukemia. The diagnosis of MDS can be difficult; there is a paucity of molecular markers, and the pathophysiology is largely unknown. Therefore, we conducted a multicenter study investigating whether serum proteome profiling may serve as a noninvasive platform to discover novel molecular markers for MDS. We generated serum proteome profiles from 218 individuals by MS and identified a profile that distinguishes MDS from non-MDS cytopenias in a learning sample set. This profile was validated by testing its ability to predict MDS in a first independent validation set and a second, prospectively collected, independent validation set run 5 months apart. Accuracy was 80.5% in the first and 79.0% in the second validation set. Peptide mass fingerprinting and quadrupole TOF MS identified two differential proteins: CXC chemokine ligands 4 (CXCL4) and 7 (CXCL7), both of which had significantly decreased serum levels in MDS, as confirmed with independent antibody assays. Western blot analyses of platelet lysates for these two platelet-derived molecules revealed a lack of CXCL4 and CXCL7 in MDS. Subtype analyses revealed that these two proteins have decreased serum levels in advanced MDS, suggesting the possibility of a concerted disturbance of transcription or translation of these chemokines in advanced MDS.

[1]  M. Albitar,et al.  Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome , 2005, Cancer.

[2]  J. Damilakis,et al.  Serum Evaluation of Angiogenic Cytokines Basic Fibroblast Growth Factor, Hepatocyte Growth Factor and TNF-ALPHA in Patients with Myelodysplastic Syndromes: Correlation with Bone Marrow Microvascular Density , 2005, International journal of immunopathology and pharmacology.

[3]  H. Otu,et al.  Optimization and evaluation of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) with reversed-phase protein arrays for protein profiling , 2005, Clinical chemistry and laboratory medicine.

[4]  J. Shay,et al.  Lack of mutations of the human telomerase RNA gene (hTERC) in myelodysplastic syndrome. , 2005, Haematologica.

[5]  D. Chan,et al.  Evaluation of serum protein profiling by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry for the detection of prostate cancer: I. Assessment of platform reproducibility. , 2005, Clinical chemistry.

[6]  Marie Joseph,et al.  Gene expression signature with independent prognostic significance in epithelial ovarian cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  S. Gettinger,et al.  Complications of therapy in cancer patients: Case 2. Scrotal ulceration during all-trans-retinoic acid therapy for acute promyelocytic leukemia. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  R. Bast,et al.  Three Biomarkers Identified from Serum Proteomic Analysis for the Detection of Early Stage Ovarian Cancer , 2004, Cancer Research.

[9]  M. Lübbert,et al.  DNA Methylation as a Therapeutic Target in Hematologic Disorders: Recent Results in Older Patients with Myelodysplasia and Acute Myeloid Leukemia , 2004, International journal of hematology.

[10]  Gustavo Stolovitzky,et al.  Genes@Work: an efficient algorithm for pattern discovery and multivariate feature selection in gene expression data , 2004, Bioinform..

[11]  D. Ransohoff.  Rules of evidence for cancer molecular-marker discovery and validation , 2004, Nature Reviews Cancer.

[12]  Platelet function and its clinical significance in the myelodysplastic syndromes. , 2004, The hematology journal : the official journal of the European Haematology Association.

[13]  J. Glimm,et al.  Detection of cancer-specific markers amid massive mass spectral data , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[14]  K. Kozak,et al.  Identification of biomarkers for ovarian cancer using strong anion-exchange ProteinChips: Potential use in diagnosis and prognosis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Arkadiusz Z Dudek,et al.  Platelet factor 4 promotes adhesion of hematopoietic progenitor cells and binds IL-8: novel mechanisms for modulation of hematopoiesis. , 2003, Blood.

[16]  G. Mufti,et al.  Apoptosis in the myelodysplastic syndromes. , 2003, Current hematology reports.

[17]  T. Yip,et al.  Comprehensive proteomic profiling identifies serum proteomic signatures for detection of hepatocellular carcinoma and its subtypes. , 2003, Clinical chemistry.

[18]  D. Steensma,et al.  The myelodysplastic syndrome(s): a perspective and review highlighting current controversies. , 2003, Leukemia research.

[19]  M. Radmacher,et al.  Pitfalls in the use of DNA microarray data for diagnostic and prognostic classification. , 2003, Journal of the National Cancer Institute.

[20]  Yudong D. He,et al.  A Gene-Expression Signature as a Predictor of Survival in Breast Cancer , 2002 .

[21]  E. Dalmasso,et al.  Contribution of Human α-Defensin 1, 2, and 3 to the Anti-HIV-1 Activity of CD8 Antiviral Factor , 2002, Science.

[22]  C. Ho,et al.  Circulating Levels of Thrombopoietic and Inflammatory Cytokines in Patients with Acute Myeloblastic Leukemia and Myelodysplastic Syndrome , 2002, Oncology.

[23]  D. Chan,et al.  Proteomics and bioinformatics approaches for identification of serum biomarkers to detect breast cancer. , 2002, Clinical chemistry.

[24]  P. Schellhammer,et al.  Serum protein fingerprinting coupled with a pattern-matching algorithm distinguishes prostate cancer from benign prostate hyperplasia and healthy men. , 2002, Cancer research.

[25]  E. Petricoin,et al.  Use of proteomic patterns in serum to identify ovarian cancer , 2002, The Lancet.

[26]  Yudong D. He,et al.  Gene expression profiling predicts clinical outcome of breast cancer , 2002, Nature.

[27]  C. Masters,et al.  The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Y. Tu,et al.  Gene Expression Profiling of B Cell Chronic Lymphocytic Leukemia Reveals a Homogeneous Phenotype Related to Memory B Cells , 2001, The Journal of experimental medicine.

[29]  M S Pepe,et al.  Phases of biomarker development for early detection of cancer. , 2001, Journal of the National Cancer Institute.

[30]  U. Germing,et al.  Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients. , 2000, Leukemia research.

[31]  J. Bennett,et al.  World Health Organization classification of the acute leukemias and myelodysplastic syndrome. , 2000, International journal of hematology.

[32]  Andrea Califano,et al.  SPLASH: structural pattern localization analysis by sequential histograms , 2000, Bioinform..

[33]  J. Mesirov,et al.  Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. , 1999, Science.

[34]  A. Órfão,et al.  Myelodysplastic syndrome: a search for minimal diagnostic criteria. , 1999, Leukemia research.

[35]  Z. Han,et al.  Platelet factor 4 and other CXC chemokines support the survival of normal hematopoietic cells and reduce the chemosensitivity of cells to cytotoxic agents. , 1997, Blood.

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

[37]  N. Rosenthal,et al.  Myelodysplastic syndromes and acute myeloid leukemia in connective tissue disease after single-agent chemotherapy. , 1996, American journal of clinical pathology.

[38]  H. Flad,et al.  TNF-alpha renders human neutrophils responsive to platelet factor 4. Comparison of PF-4 and IL-8 reveals different activity profiles of the two chemokines. , 1996, Journal of immunology.

[39]  M. Ratajczak,et al.  Chemokine regulation of human megakaryocytopoiesis. , 1995, Blood.

[40]  J. Vermylen,et al.  Platelet ultrastructural and functional studies in myelodysplasia. , 1995, Haematologia.

[41]  D. Oscier,et al.  Establishing the incidence of myelodysplastic syndrome. , 1994, British journal of haematology.

[42]  N. Gattermann,et al.  Age‐related incidence and other epidemiological aspects of myelodysplastic syndromes , 1992, British journal of haematology.

[43]  F. McCormick,et al.  Retrospective analysis of ras gene activation in myeloid leukemic cells. , 1990, Oncogene.

[44]  M. Baggiolini,et al.  Generation of the neutrophil-activating peptide NAP-2 from platelet basic protein or connective tissue-activating peptide III through monocyte proteases , 1990, The Journal of experimental medicine.

[45]  V. Menys,et al.  The myelodysplastic syndromes--a study of haemostatic function and platelet ultrastructure. , 2009, Scandinavian journal of haematology.

[46]  W. Vainchenker,et al.  Immunological study of in vitro maturation of human megakaryocytes , 1984, British journal of haematology.

[47]  P. Greenberg.  The smoldering myeloid leukemic states: clinical and biologic features. , 1983, Blood.

[48]  J F Fries,et al.  The 1982 revised criteria for the classification of systemic lupus erythematosus. , 1982, Arthritis and rheumatism.

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

[50]  A. Chapelle,et al.  Defective chemotaxis in monosomy-7 , 1977, Nature.