Superfund Research Program

Biomarkers of Carcinogenesis

Project Leader: Martyn T. Smith
Grant Number: P42ES004705
Funding Period: 1995 - 2006

Project-Specific Links

Final Progress Reports

Year:   2005 

Leukemia is the most common form of cancer in children, representing 31% of childhood cancers. In the US, 2400 new cases of acute lymphoblastic leukemia (ALL) are diagnosed each year. Leukemias are classified into different subtypes on the basis of their immunophenotypic and cytogenetic characteristics, and have variable prognoses and most likely differing etiologies. For example, ALL is more common in children than acute myeloid leukemia (AML). Recently, various groups have begun to apply cDNA microarrays in an attempt to subclassify childhood leukemias with some success. In particular, distinct patterns of gene expression have been shown to differentiate between ALL and AML subtypes. Proteome analysis of childhood leukemia subtypes may yield similar results and further aide the diagnostic process, as well as increase the precision of epidemiologic studies to detect associations between subtypes of leukemia with environmental exposures. Proteome analysis measures all detectable proteins in a biological sample. In a Leading Article in the journal Leukemia in September 2005, Drs. Smith and Wiencke reported that proteomic analysis by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) could be used to analyze differentially expressed proteins in different subtypes of childhood leukemia (Hegedus CM et al, 2005). The results further demonstrated the potential for proteomics to discover altered proteins involved in the development of leukemias, including a C-terminal truncated form of ubiquitin.

The research team has also used array-based SELDI-TOF MS proteomics to discover biomarkers in chemically exposed populations. For example, benzene is a ubiquitous environmental contaminant and is known to have toxic effects on the blood and bone marrow. It has been found at over half of the National Priorities List sites identified by the Environmental Protection Agency. The researchers recently reported in the Proceedings of the National Academy of Sciences that three proteins (4.1, 7.7, and 9.3 kDa) were down-regulated in benzene exposed subjects (Vermeulen R et al, 2005). The 7.7- and 9.3-kDa proteins were subsequently identified as platelet factor (PF)4 and connective tissue activating peptide (CTAP)-III. Initial proteomic results for PF4 and CTAP-III were subsequently confirmed in a single experiment using a ProteinChip-array-based immunoassay. Lowered expression of PF4 and CTAP-III proteins is a potential biomarker of benzene's early biologic effects and may play a role in the immunosuppressive effects of benzene. These findings also provide important insight into the mechanisms by which benzene may produce AML.