Jan. 15, 2007 Scientists have identified a set of biomarkers that could help clinicians identify a group of hematologic malignancies known as myelodysplastic syndromes (MDS), which affect approximately 300,000 individuals worldwide and often progress to acute myeloid leukemia.
Reported in the advance issue of the Proceedings of the National Academy of Sciences (which appears on-line the week of January 8) the findings point to a possible new diagnostic method for these malignancies, which occur when blood cells remain in an immature stage within the bone marrow and never sufficiently develop into the mature cells necessary for proper hematologic functioning. The study was led by researchers at Beth Israel Deaconess Medical Center (BIDMC) and Heinrich Heine University in Duesseldorf, Germany.
"Currently, a bone marrow biopsy is the only definitive means available to diagnose MDS," explains senior author Towia Libermann, PhD, Director of the Genomics Center at BIDMC and director of the Dana-Farber/Harvard Cancer Center Cancer Proteomics Core. "And since this group of malignancies primarily affects elderly patients, such a procedure is particularly arduous and sometimes impossible."
Therefore, first author Manuel Aivado, MD, PhD, a member of the Libermann laboratory and Lecturer in Medicine at Harvard Medical School (HMS), devised a clinical study to test whether serum proteomic profiling might be used to identify biomarkers for MDS.
The large-scale study of proteins -- including their expression, modification, composition, structure and function -- the field of proteomics is proving instrumental in the identification of molecular biomarkers, such as those that indicate a particular disease, according to Libermann, who is also Associate Professor of Medicine at HMS.
Aivado and Libermann used a combination of two technologies -- protein fractionation and mass spectrometry -- to create proteome profiles from the serum of 218 patients (representing clinical trial participants from both the MDS Study Group in Duesseldorf and from BIDMC). Through these profiles, the investigators were able to successfully distinguish between cases of MDS, healthy control subjects and cases of non-MDS-related cytopenias (blood cell disorders).
"Rather than uncovering a single biomarker, we were able to identify a protein signature [or spectrum], which reproducibly identified MDS patients among three separate and distinct patient cohorts," explains Libermann. "Since many patients with autoimmune disorders are treated with cytotoxic drugs such as azathioprine or methotrexate, they become cytopenic and may be suspected of having MDS. By using this new profile, the need for bone marrow biopsies might also be reduced among this patient population."
In the second part of the study, the authors identified two separate chemokines -- CXCL4 and CXCL7 -- the first such molecular biomarkers for advanced MDS.
"Proteomic profiling, using in-depth mass spectrometry, follows in the footsteps of genomics and represents a critical next step in understanding the pathophysiology of diseases," says Libermann. "This study demonstrated for the first time that proteomic profiling can be used for biomarker discovery and diagnostic evaluation of hematologic malignancies, an important step in refining the diagnosis and, eventually, the treatment of this devastating malignancy."
This study was funded, in part, by grants from the National Institutes of Health, as well as by Leukamic-Liga e.V., Duesseldorf, the Dr. Mildred Scheel Cancer Foundation and the Whitaker Foundation.
In addition to Libermann and Aivado, coauthors include BIDMC investigators Dimitrios Spentzos, MD, Franck Grall, PhD, Ulrich Steidl, MD, PhD, Hasan Otu, PhD, Akos Czibere, MD, Michelle Shayne, MD, and Wolf Prall, MD; Heinrich Heine University investigators Ulrich Germing, MD, Aristoteles Giagounidis, MD, Christof Iking-Konert, MD, Norbert Gattermann, MD, PhD, and Rainer Haas, MD; Harvard Partners Center for Genetics and Genomics investigators Gil Alterowitz, PhD and Marco Ramoni, PhD; Ciphergen Biosystems, Inc., investigators Xiao-Ying Meng and Eric Fung, MD, PhD; Giannoula Klement, MD, of Children's Hospital Boston; and Constantine Mitsiades, MD, of Dana-Farber/Harvard Cancer Center.
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