Biology Reference
In-Depth Information
high CI identified a cohort of patients with poor prognosis regardless of treatment
modalities, phase of presentation, and international staging system (ISS) stage. In a
separate study by Hose et al., a significant correlation between CI and survival was
not demonstrated, although sample size might account for the difference (Hose
et al.
2009
).
With regards to the molecular phenotype, no correlation between centrosome
amplification and ploidy categories was identified (Chng et al.
2006
). Gene
expression profiling (GEP) analysis comparing high versus low CI MM revealed
an overexpression of genes coding for proteins associated with the centrosome
(TUBG1, CETN2, TACC3, NEK2, PRKRA, STK6, AURKB and PLK4), cell cycle
(CCNB1, CCNB2, CCND2, E2F2, CDC gene family, CDK5, CDK6, CDKN2C),
proliferation (RAN, CSK1B, TOP2A, TTK, TYMS, MCM gene family, ASPM),
DNA repair/G2 cell cycle checkpoints (BRCA1, CHEK1, CHEK2, MAD2L1,
BUB1, BUB1B, FANCD2, REV1L), and kinetochore and microtubule attachment
(BIRC5, CENPA, CENPE, CENPH, ZWINT) (Chng et al.
2008
). Centrosome
amplification is therefore associated with abnormalities of the cell cycle, prolif-
eration, and DNA repair in MM, findings very similar to a separate study on
centrosome aberrations in acute myeloid leukemia (Neben et al.
2004
).
15.6 Possible Mechanisms Leading to Centrosome
Amplification in MM
Proteins that participate in the regulation of chromosomal numerical integrity
belong to one of three functional groups: cell-cycle regulation, DNA-damage
response/repair,
and
nucleocytoplasmic
transport.
Mutations
involving
these
proteins lead to supernumerary centrosomes (Fukasawa
2007
).
To date, direct mechanisms leading to centrosome amplification in MM have
not been identified. Table
15.1
provides a list of molecules that are known to
participate in centrosome function/regulation of centrosome number, and that have
been separately implicated in MM pathogenesis as well. We discuss in-depth the
G1 cyclin-CDK/Rb pathway, receptor of hyalorunan-mediated motility
(RHAMM), and Aurora-A molecules which we feel represent important causative
factors underlying centrosome amplification in MM.
15.7 G1 Cyclin-CDK/Rb Pathway
The centrosome duplication cycle is tightly linked to the cell division cycle, and the
G1 cyclins (D and E) and their associated kinases (Lee and Yang
2003
; Sherr and
Roberts
2004
; Giacinti and Giordano
2006
) play integral roles in both processes
(Bettencourt-Dias and Glover
2007
). D-type cyclins associate with CDK4 or CDK6
and function early in G1-phase, while cyclin E associates with CDK2 and functions
