Biology Reference
In-Depth Information
15.3 Centrosomal Abnormalities as a Mechanism
for Aneuploidy in Multiple Myeloma
The high prevalence of aneuploidy and evolving genetic complexity during disease
progression seen in MM (Wu et al.
2007
) strongly suggest that the MM genome is
unstable, and specifically points to the presence of chromosomal instability (CIN)
in MM pathogenesis. CIN is a phenomenon in which cells persistently demonstrate
a high rate of loss and gain of whole chromosomes, and one mechanism leading to
CIN is numerical centrosome anomalies (Thompson et al.
2010
).
Centrosomes are the primary microtubule-organizing center (MTOC) in animal
cells, and facilitate organization of the spindle poles during mitosis (Bettencourt-
Dias and Glover
2007
). A causal association between centrosome abnormalities
and cancer was first proposed by Boveri in the early 1900s (Boveri
1914
,
2008
).
Centrosome aberrations are frequent in various cancer types (Pihan et al.
1998
)
and are already present in some early premalignant lesions (Pihan et al.
2003
).
There is recent evidence for a causal link between centrosome anomalies and
numerical chromosomal abnormalities (Nigg and Raff
2009
; Thompson et al.
2010
). One proposed mechanism by which supernumerary centrosomes promote
tumorigenesis is through aberrant spindle formation during cell division, resulting
in CIN and aneuploidy. Cells with amplified centrosomes may form tripolar
mitotic spindles and undergo cytokinesis to generate viable but highly aneuploid
daughters (Fukasawa
2008
).
Mitotic spindles with more than three poles may also be formed, resulting in
cytokinesis failure. In the presence of p53, this failure to undergo cytokinesis
triggers the checkpoint response, leading ultimately to cell death (Fukasawa
2008
).
Mitotic clustering of centrosomes with pseudo-bipolar spindle formation is one
mechanism by which multipolar divisions in cancer cells are suppressed (Kwon
et al.
2008
; Quintyne et al.
2005
). Centrosome amplification can still lead to
chromosome missegregation due to an increased rate of merotely, where a single
sister
kinetochore
becomes
simultaneously
attached
to
two
spindle
poles
(Silkworth et al.
2009
; Ganem et al.
2009
).
MM also exhibits genomic instability in the form of structural chromosomal
abnormalities such as deletions and translocations. There is at present little
evidence to suggest that centrosomes play a significant causative role in the
development of these abnormalities.
15.4 Centrosome Abnormalities in MM
Three studies have examined centrosome abnormalities in MM (Maxwell et al.
2005
; Dementyeva et al.
2010
; Chng et al.
2006
). To evaluate structural and
numerical centrosome abnormalities, Maxwell et al. (Maxwell et al.
2005
)
performed multicolor immunofluorescence on archived bone marrow core biopsies
