Biology Reference
In-Depth Information
related to centrosomal abnormalities in MM as p27 has been shown to suppress
centrosome amplification following DNA damage (Sugihara et al.
2006
).
While abnormalities affecting the Rb pathway are almost universal and early
events in MM, there is at present no convincing evidence that such abnormalities
are causal for centrosome amplification in MM, and centrosome amplification is
not seen in all MM patients. However, these abnormalities may create a permissive
environment for centrosome amplification.
15.8 Receptor of Hyalorunan-Mediated Motility
RHAMM is a cell-motility molecule first described by Turley and colleagues
(Turley
1992
; Turley and Torrance
1985
; Turley et al.
1987
,
1991
), and the human
full-length cDNA was cloned in 1996 (Wang et al.
1996
). RHAMM overexpres-
sion in fibroblasts induces transformation (Hall et al.
1995
), and RHAMM-hya-
luronan interactions have been shown to mediate the activation of oncogenic
kinases such as Src, extracellular-regulated kinases (Erk), and protein kinase C
(Turley et al.
2002
). RHAMM also localizes to the centrosome and functions in the
maintenance of spindle integrity (Maxwell et al.
2003
).
Existing evidence suggests that RHAMM plays an important role in MM
pathogenesis. MM plasma cells were first observed to express RHAMM by Turley
et al. in 1993 (Turley et al.
1993
). Novel RHAMM variants were later identified
and shown to be overexpressed in MM plasma cells relative to normal B cells
(Crainie et al.
1999
). Increasing RHAMM expression in MM strongly correlated
with osteolytic bone lesions (Zhan et al.
2002
), poor event-free, and overall
survival (Maxwell et al.
2004
).
As mentioned previously, structural and numerical centrosomal abnormalities
in MM cells were first identified by Maxwell et al. (
2005
). They also found that
structural centrosomal abnormalities correlated with elevated RHAMM expression
in MM. RHAMM overexpression in vitro resulted in altered centrosome size and
structure. Although the mechanism by which RHAMM affected centrosome
structure was not elucidated in detail, a link between RHAMM, TPX2, and Aurora
A (see next section) was proposed because RHAMM was found to colocalize and
coimmunoprecipitate TPX2 in a cell cycle-dependent manner. Further evidence
for a RHAMM-TPX2-Aurora A pathway is seen in a later study which showed that
RHAMM overexpression and silencing in vitro in a MM cell line resulted in
enhanced and decreased sensitivity respectively to treatment with Aurora kinase-
specific inhibitors (Shi et al.
2007
).
The reason for elevated RHAMM in MM is also uncertain. The gene encoding
RHAMM, HMMR, is located on chromosome 5q33. Although chromosome 5
trisomy is common and might account for the elevated expression of RHAMM in
H-MM, RHAMM overexpression is more strongly associated with NH-MM. Also
H-MM is associated with a better prognosis, while increasing RHAMM expression
