RHAMM expression and isoform balance predict aggressive disease and poor survival in multiple myeloma.
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 (RHAMMFL) 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/RHAMMFL 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/RHAMMFL ratio. Absolute RHAMM expression and the RHAMM-exon4/RHAMMFL 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/RHAMMFL ratio increases with disease burden. The RHAMM-exon4/RHAMMFL 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.
Maxwell
Christopher A
CA
Department of Medical Oncology, Cross Cancer Institute, 11560 University Ave, Edmonton, AB, T6G 1Z2, Canada.
Rasmussen
Erik
E
Zhan
Fenghuang
F
Keats
Jonathan J
JJ
Adamia
Sophia
S
Strachan
Erin
E
Crainie
Mary
M
Walker
Ronald
R
Belch
Andrew R
AR
Pilarski
Linda M
LM
Barlogie
Bart
B
Shaughnessy
John
J
Reiman
Tony
T
D000368:Aged; D016326:Extracellular Matrix Proteins / Q000032:analysis / Q000097:blood / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D008938:Mitosis; D009101:Multiple Myeloma / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality; D011379:Prognosis; D020033:Protein Isoforms / Q000032:analysis / Q000097:blood; D012334:RNA, Neoplasm / Q000032:analysis; D016019:Survival Analysis; D015996:Survival Rate
D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D020033:Protein Isoforms; D012334:RNA, Neoplasm; C098946:hyaluronan-mediated motility receptor