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from mid to late G1-phase (Lee and Yang 2003 ). Their activation leads to phos-
phorylation of the retinoblastoma (Rb) protein, the main molecule responsible for the
G1 checkpoint, and entry into S-phase (Giacinti and Giordano 2006 ).
The CDK2-cyclin E kinase complex is an important initiator of centrosome
duplication (Lacey et al. 1999 ; Hinchcliffe et al. 1999 ), and its centrosomal target
proteins include nucleophosmin (Okuda et al. 2000 ), Mps1 kinase (Fisk and Winey
2001 ), and CP110 (Chen et al. 2002 ). Cyclin E overexpression alone does not lead
to centrosomal amplification in vitro (Spruck et al. 1999 ). CDK2 has recently been
demonstrated to be important for centrosome amplification in p53-null mouse
embryonic fibroblasts (Adon et al. 2010 ). At present however, there is no
demonstrated role for the CDK2-cyclin E complex in MM centrosomal amplifi-
cation or pathogenesis.
CDK4 has also been implicated in centrosome amplification in p53-null cells
(Adon et al. 2010 ), and cyclin D overexpression induces centrosome amplification
in hepatocytes (Nelsen et al. 2005 ). Abnormalities of the cyclin D-Rb axis with
increased and/or dysregulated expression of cyclins D1, D2, or D3 are seen in
nearly all genetic subtypes of MM (Bergsagel et al. 2005 ). t(11; 14) and t(6; 14)
lead directly to overexpression of cyclins D1 and D3 respectively. t(4; 14) MM
shows cyclin D2 overexpression. As cyclin D2 is a transcriptional target of
maf, maf-translocated MM also shows cyclin D2 overexpression (Hurt et al. 2004 ).
H-MM shows overexpression of cyclins D1 and/or D2. These abnormalities of the
cyclin D-Rb axis lead to inactivation of Rb and facilitate cell cycle dysregulation
in MM (Ely et al. 2005 ).
Loss of Rb function also results in centrosome amplification (Iovino et al. 2006 ;
Duensing et al. 2000 ; Balsitis et al. 2003 ). Rb is located on chromosome 13q14.2, and
chromosome 13 abnormalities are detected in 50 % of MM cases. Eighty-five
percentage of these abnormalities are monosomy, and the remainder are interstitial
deletions (Fonseca et al. 2009 ). Heterozygous deletions of Rb have been reported in
MM (Juge-Morineau et al. 1997 ; Kramer et al. 2002 ). However, a direct link between
loss of Rb function and centrosome amplification in MM has not been demonstrated.
Other abnormalities of the Rb pathway are also seen in MM. CDK inhibitors
such as p15, p16, p17, and p18 specifically suppress cyclin D kinase activity, while
p21 and p27 act on other cyclin/CDK complexes (Giacinti and Giordano 2006 ).
Methylation of the p15 and p16 genes is observed in around 20-30 % of MGUS/
MM and in most human myeloma cell lines (HMCL) (Fonseca et al. 2004 , 2009 ).
Also, p16 expression is low to absent in most MM independent of methylation
status (Gonzalez-Paz et al. 2007 ; Dib et al. 2007 ).
Various lines of evidence suggest that loss of function of other CDK inhibitors
occurs in MM. Bi-allelic deletion of p18, a gene that is important for normal B-cell
development (Morse et al. 1997 ; Ashihara et al. 2009 ; Schrantz et al. 2000 ), has
been observed in HMCL and primary MM cases, and exogenous p18 expression
inhibits growth of HMCL with low/absent endogenous p18 expression (Dib et al.
2006 ). Low p27 expression is reportedly an independent adverse prognostic factor
in MM patients (Filipits et al. 2003 ); interestingly, loss of p27 function might be
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