Abstract
Chronic lymphocytic leukemia (CLL) is a common hematopoietic malignant disease with variable outcome. CLL has been divided into distinct groups based on whether somatic hypermutation has occurred in the variable region of the immunoglobulin heavy-chain locus or alternatively if the cells express higher levels of the CD38 protein. We have analyzed the proteome of 12 cases of CLL (six mutated (M-CLL) and six unmutated (UM-CLL) immunoglobulin heavy-chain loci; seven CD38-negative and five CD38-positive) using two-dimensional electrophoresis and mass spectrometry. Statistical evaluation using principal component analysis indicated significant differences in patterns of protein expression between the cases with and without somatic mutation. Specific proteins indicated by principal component analysis as varying between the prognostic groups were characterized using mass spectrometry. The levels of F-actin-capping protein beta subunit, 14-3-3 beta protein, and laminin-binding protein precursor were significantly increased in M-CLL relative to UM-CLL. In addition, primary sequence data from tandem mass spectrometry showed that nucleophosmin was present as several protein spots in M-CLL but was not detected in UM-CLL samples, suggesting that several post-translationally modified forms of nucleophosmin vary between these two sample groups. No specific differences were found between CD38-positive and -negative patient samples using the same approach. The results presented show that proteomic analysis can complement other approaches in identifying proteins that may have potential value in the biological and diagnostic distinction between important clinical subtypes of CLL.
Highlights
Chronic lymphocytic leukemia (CLL) is a common hematopoietic malignant disease with variable outcome
Using principal component analysis (PCA) of 2D gels we have shown differential expression of proteins between UM-CLL and MCLL samples, identifying potential marker proteins associated with these different CLL subtypes and thereby revealing potential value in this approach to the characterization of leukemia subtypes
The immunoglobulin heavy-chain locus (Ig VH) gene expressed and its mutation status are shown for each patient
Summary
Chronic lymphocytic leukemia (CLL) is a common hematopoietic malignant disease with variable outcome. CLL has been divided into distinct groups based on whether somatic hypermutation has occurred in the variable region of the immunoglobulin heavy-chain locus or alternatively if the cells express higher levels of the CD38 protein. Specific proteins indicated by principal component analysis as varying between the prognostic groups were characterized using mass spectrometry. Genes whose expression levels significantly correlate with patient survival and/or with clinical staging have been found and categorized as encoding or potentiating activity of cell adhesion molecules [15]. It remains to be seen if these proteins or their gene transcripts have value as disease markers. Ig VH, immunoglobulin heavy-chain locus; M-CLL, CLL with somatic mutation of Ig VH; UM-CLL, CLL without somatic mutation of Ig VH; MALDI-ToF, matrix-assisted laser desorption ionization time-of-flight; PCA, principal component analysis; 2D, two-dimensional; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid
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