Serum proteome profiling detects myelodysplastic syndromes and identifies CXC chemokine ligands 4 and 7 as markers for advanced disease
- Manuel Aivado*,†,‡,
- Dimitrios Spentzos*,†,§,
- Ulrich Germing‡,
- Gil Alterovitz¶,
- Xiao-Ying Meng‖,
- Franck Grall*,†,
- Aristoteles A. N. Giagounidis‡,
- Giannoula Klement**,
- Ulrich Steidl†,‡,
- Hasan H. Otu†,††,
- Akos Czibere*,†,
- Wolf C. Prall*,†,
- Christof Iking-Konert‡‡,
- Michelle Shayne§,
- Marco F. Ramoni¶,
- Norbert Gattermann‡,
- Rainer Haas‡,
- Constantine S. Mitsiades§§,
- Eric T. Fung‖, and
- Towia A. Libermann*,†,¶¶
- *Proteomics Core and
- §§Department of Medical Oncology, Dana–Farber/Harvard Cancer Center, Boston, MA 02115;
- †Genomics Center and
- §Division of Hematology and Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;
- ‡Departments of Hematology, Oncology and Clinical Immunology and
- ‡‡Rheumatology, Heinrich Heine University, 40225 Duesseldorf, Germany;
- ¶Children's Hospital Informatics Program, Harvard Partners Center for Genetics and Genomics, Boston, MA 02115;
- ‖Ciphergen Biosystems, Inc., Fremont, CA 94555; and
- **Pediatric Neuro-Oncology, Children's Hospital, Boston, MA 02115
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Communicated by Joseph Schlessinger, Yale University School of Medicine, New Haven, CT, November 22, 2006 (received for review March 13, 2006)
Abstract
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.
Footnotes
- ¶¶To whom correspondence should be addressed. E-mail: tliberma{at}bidmc.harvard.edu
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↵ ††Present address: Department of Genetics and Bioengineering, Yeditepe University, Istanbul 34755, Turkey.
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Author contributions: M.A., D.S., U.G., N.G., R.H., and T.A.L. designed research; M.A., X.-Y.M., F.G., G.K., A.C., W.C.P., C.I.-K., M.S., and E.T.F. performed research; U.G., A.A.N.G., C.I.-K., M.S., and N.G. contributed new reagents/analytic tools; M.A., D.S., G.A., F.G., U.S., H.H.O., M.F.R., C.S.M., and T.A.L. analyzed data; and M.A., D.S., U.G., F.G., U.S., H.H.O., R.H., C.S.M., E.T.F., and T.A.L. wrote the paper.
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The authors declare no conflict of interest.
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See Commentary on page 1109.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0610330104/DC1.
- Abbreviations:
- MDS,
- myelodysplastic syndrome;
- CXCL,
- CXC chemokine ligand;
- BM,
- bone marrow;
- FAB,
- French–American–British;
- SELDI-TOF-MS,
- surface-enhanced laser desorption/ionization TOF MS;
- WHO,
- World Health Organization;
- k-nn,
- k nearest neighbor;
- RA,
- refractory anemia;
- RAEB,
- RA with excess of blasts;
- LDH,
- lactate dehydrogenase.
- © 2007 by The National Academy of Sciences of the USA
