Total proteome analysis identifies migration defects as a major pathogenetic factor in immunoglobulin heavy chain variable region (IGHV)-unmutated chronic lymphocytic leukemia

Gina L. Eagle, Jianguo Zhuang, Rosalind E. Jenkins, Kathleen J. Till, Puthen V. Jithesh, Ke Lin, Gillian G. Johnson, Melanie Oates, Kevin Park, Neil R. Kitteringham, Andrew R. Pettitt

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The mutational status of the immunoglobulin heavy chain variable region defines two clinically distinct forms of chronic lymphocytic leukemia (CLL) known as mutated (M-CLL) and unmutated (UM-CLL). To elucidate the molecular mechanisms underlying the adverse clinical outcome associated with UM-CLL, total proteomes from nine UM-CLL and nine M-CLL samples were analyzed by isobaric tags for relative and absolute quantification (iTRAQ)-based mass spectrometry. Based on the expression of 3521 identified proteins, principal component analysis separated CLL samples into two groups corresponding to immunoglobulin heavy chain variable region mutational status. Computational analysis showed that 43 cell migration/adhesion pathways were significantly enriched by 39 differentially expressed proteins, 35 of which were expressed at significantly lower levels in UM-CLL samples. Furthermore, UM-CLL cells underexpressed proteins associated with cytoskeletal remodeling and overexpressed proteins associated with transcriptional and translational activity. Taken together, our findings indicate that UM-CLL cells are less migratory and more adhesive than M-CLL cells, resulting in their retention in lymph nodes, where they are exposed to proliferative stimuli. In keeping with this hypothesis, analysis of an extended cohort of 120 CLL patients revealed a strong and specific association between UM-CLL and lymphadenopathy. Our study illustrates the potential of total proteome analysis to elucidate pathogenetic mechanisms in cancer.

Original languageEnglish
Pages (from-to)933-945
Number of pages13
JournalMolecular and Cellular Proteomics
Volume14
Issue number4
DOIs
Publication statusPublished - 1 Apr 2015
Externally publishedYes

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Immunoglobulin Heavy Chains
B-Cell Chronic Lymphocytic Leukemia
Proteome
Defects
Proteins
Principal component analysis
Mass spectrometry
Adhesives
Adhesion
Principal Component Analysis
Cell Adhesion
Cell Movement
Mass Spectrometry
Cohort Studies
Lymph Nodes
Neoplasms

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Molecular Biology

Cite this

Total proteome analysis identifies migration defects as a major pathogenetic factor in immunoglobulin heavy chain variable region (IGHV)-unmutated chronic lymphocytic leukemia. / Eagle, Gina L.; Zhuang, Jianguo; Jenkins, Rosalind E.; Till, Kathleen J.; Jithesh, Puthen V.; Lin, Ke; Johnson, Gillian G.; Oates, Melanie; Park, Kevin; Kitteringham, Neil R.; Pettitt, Andrew R.

In: Molecular and Cellular Proteomics, Vol. 14, No. 4, 01.04.2015, p. 933-945.

Research output: Contribution to journalArticle

Eagle, Gina L. ; Zhuang, Jianguo ; Jenkins, Rosalind E. ; Till, Kathleen J. ; Jithesh, Puthen V. ; Lin, Ke ; Johnson, Gillian G. ; Oates, Melanie ; Park, Kevin ; Kitteringham, Neil R. ; Pettitt, Andrew R. / Total proteome analysis identifies migration defects as a major pathogenetic factor in immunoglobulin heavy chain variable region (IGHV)-unmutated chronic lymphocytic leukemia. In: Molecular and Cellular Proteomics. 2015 ; Vol. 14, No. 4. pp. 933-945.
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