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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1684-1696
Overexpression of the Receptor for Hyaluronan-Mediated Motility
(RHAMM) Characterizes the Malignant Clone in Multiple Myeloma:
Identification of Three Distinct RHAMM Variants
Mary Crainie,
Andrew R. Belch,
Michael J. Mant, and
Linda M. Pilarski
From the Departments of Oncology and Medicine, University of Alberta
and the Cross Cancer Institute, Edmonton, Canada.
The receptor for hyaluronan (HA)-mediated motility (RHAMM) controls
motility by malignant cells in myeloma and is abnormally expressed on
the surface of most malignant B and plasma cells in blood or bone
marrow (BM) of patients with multiple myeloma (MM). RHAMM cDNA was
cloned and sequenced from the malignant B and plasma cells comprising
the myeloma B lineage hierarchy. Three distinct RHAMM gene products,
RHAMMFL, RHAMM 48, and
RHAMM147, were cloned from MM B and plasma cells.
RHAMMFL was 99% homologous to the published sequence of
RHAMM. RHAMM48 and RHAMM147 variants
align with RHAMMFL, but are characterized by sequence
deletions of 48 bp (16 amino acids [aa]) and 147 bp (49 aa),
respectively. The relative frequency of these RHAMM transcripts in MM
plasma cells was determined by cloning of reverse-transcriptase
polymerase chain reaction (RT-PCR) products amplified from MM plasma
cells. Of 115 randomly picked clones, 49% were RHAMMFL,
47% were RHAMM48, and 4% were RHAMM147.
All of the detected RHAMM variants contain exon 4, which is alternatively spliced in murine RHAMM, and had only a single copy of
the exon 8 repeat sequence detected in murine RHAMM. RT-PCR analysis of
sorted blood or BM cells from 22 MM patients showed that overexpression
of RHAMM variants is characteristic of MM B cells and BM plasma cells
in all patients tested. RHAMM also appeared to be overexpressed in B
lymphoma and B-chronic lymphocytic leukemia (CLL) cells. In B cells
from normal donors, RHAMMFL was only weakly detectable in
resting B cells from five of eight normal donors or in chronically
activated B cells from three patients with Crohn's disease.
RHAMM48 was detectable in B cells from one of eight
normal donors, but was undetectable in B cells of three donors with
Crohn's disease. RHAMM147 was undetectable in normal
and Crohn's disease B cells. In situ RT-PCR was used to determine the
number of individual cells with aggregate RHAMM transcripts. For six
patients, 29% of BM plasma cells and 12% of MM B cells had detectable
RHAMM transcripts, while for five normal donors, only 1.2% of B cells
expressed RHAMM transcripts. This work suggests that
RHAMMFL, RHAMM48, and
RHAMM147 splice variants are overexpressed in MM and
other B lymphocyte malignancies relative to resting or in
vivo-activated B cells, raising the possibility that RHAMM and its
variants may contribute to the malignant process in B-cell malignancies
such as lymphoma, CLL, and MM.
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