RHAMM expression and isoform balance predict aggressive disease and poor survival in multiple myeloma
Christopher A. Maxwell, Erik Rasmussen, Fenghuang Zhan, Jonathan J. Keats, Sophia Adamia, Erin Strachan, Mary Crainie, Ronald Walker, Andrew R. Belch, Linda M. Pilarski, Bart Barlogie, John Shaughnessy Jr, and Tony Reiman
Blood 104:1151–1158, August 2004

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Multiple myeloma (MM) plasma cells (PCs) express receptor for hyaluronan-mediated motility (RHAMM), a hyaluronan-binding, cytoskeleton and centrosome protein. The most abundant RHAMM isoforms in MM are full-length RHAMM (RHAMM^FL) and the splice variant RHAMM^-exon4. We separately examined the significance of RHAMM expression, and isoform balance, in 2 groups of MM patients. In oligonucleotide microarray experiments (n=210, Arkansas), increasing RHAMM mRNA expression in MM PCs is strongly associated with osteolytic bone lesions (P<.001), and event-free (P=.05) and overall (P=.04) survival. Semiquantitative determination of RHAMM isoform expression (Alberta, Canada) used capillary electrophoretic detection and measurement of RHAMM^-exon4/RHAMM^FL reverse-transcriptase–polymerase chain reaction (RT-PCR) products. RHAMM isoforms are rarely expressed concurrently in single MM PCs; the pattern of isoform expression, at the single-cell level, is approximated in larger numbers of cells by the RHAMM^-exon4/RHAMM^FL ratio. Absolute RHAMM expression and the RHAMM^-exon4/RHAMM^FL ratio are only partially correlated in MM PCs; in cell lines, absolute RHAMM expression is elevated in mitosis, while RHAMM ratios remain stable. Temporal examination of MM patients’ peripheral blood reveals that the RHAMM^-exon4/RHAMM^FL ratio increases with disease burden. The RHAMM^-exon4/RHAMM^FL ratio in diagnostic bone marrow samples (n=101, Alberta) is an independent prognostic factor. Thus, expression and splicing of RHAMM are important molecular determinants of disease severity in MM.

• Introduction
• Patients, materials, and methods
  • Patients and clinical data
  • Total RNA isolation, cDNA synthesis, preparation of labeled cRNA, hybridization to microarrays, and analysis of GeneChip data (Arkansas patients)
  • RNA extraction, cDNA synthesis, and RT-PCR (Alberta patients)
  • Quantitative RT-PCR (Alberta)
  • Synchronization, immunoprecipitations, and quantitation (Alberta)
  • Statistical methods
• Results
  • Increased RHAMM expression levels correlate with bone lesions, but not with DKK1 expression (Arkansas patients)
  • RHAMM expression correlates with poor disease-free and overall survival (Arkansas patients)
  • RHAMM isoforms are rarely coexpressed in individual MM plasma cells
  • RHAMM ratios measured in populations of MM PCs reflect the distribution of RHAMM isoforms seen in individual clonal cells
  • Elevated RHAMM expression, in MM patient PCs, correlates modestly with a relative increase in RHAMM^-exon4 expression
  • RHAMM expression, but not exon 4 deletion, is up-regulated during mitosis
  • RHAMM ratios in the peripheral blood reflect disease burden over time
  • High RHAMM ratios in the diagnostic bone marrow correlate with poor survival in MM
• Discussion
• References

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