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70
NG
NI 60
AIT 50
S
LL 40
CE
30
MA
AS 20
L
PF 10
O% 0
STAGE III
STAGE I
INDOLENT
MGUS
(n=15)
(n=5)
(n=6)
(n=10)

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BAD
CASPASE 9
FORKHEAD TFs
APOPTOSIS
IKK
NF-kB
ASK-1
GSK-1
P
AKT
P70S6K
S6
TSC1/TSC2
P
RIBOSOME
BIOGENESIS
EXPRESSION OF CELL
CYCLE PROTEINS
MTOR
eg., D-CYCLINS, MYC
CAP-DEPENDENT
RAPAMYCIN
P
TRANSLATION
CELL CYCLE TRANSIT
CCI-779
RAD001
4E-BP1
eIF-4E

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ANBL-6 MODEL
120
100
RAS-WT
OF
80
60
RAS-MUTANT
40
CONTROL 20
PERCENT
0
0.01
.1
1
10
100
1000
RAPAMYCIN (nM)

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MM1.S MODEL
120
myr-AKT
wt
100
80
ROL
60
CONT
40
OF
20
%
0
Control
0.10
1.00
10.00
100.00
1000.00
Rapamycin (nM)

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1
P70-P
P70-total
STAT-3-P
MM1.S-AKT MM1.S-EV
RAPA (nM)
0
0.1
1.0
10
0
0.1
1.0
10
C-MYC
C-MYC
MM1.S-AKT
MM1.S-EV

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HIGH AKT MM
LOW AKT MM
TRANSLATION
TRANSLATION
CAP-DEP
CAP-INDEP
CAP-DEP
CAP-INDEP
RAPA
HIGH AKT
RAPA
C-MYC

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IRES: INTERNAL RIBOSOMAL ENTRY SITE
5'
40S
3'
40S
IRES
CAP
5'UTR
MRNA
TRANSLATION START SITE

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pRF
SV40
SV40
Renilla
Firefly
SV40
promoter
enhancer
Luc
Luc
PolyA
C-myc 5' UTR
pRmF
2400
activity
EV
AKT
1600
luciferase
800
Relative
pRF
pRmF pRmF
pRF
pRmF pRmF
+ RAP
+ RAP

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PICTURE OF AN IRES
ITAF #2
ITAF #3
ITAF #1
40s
AUG
Translation start
codon
mRNA
ITAF #4
RIBOSOME ENTRY
WINDOW

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RAP
A AM
A YC
Y I
C N
--
--
+
+
AK
A T tu
t rned on
+
--
-
+
--
MYC ITAFS
hnRNPK
PCBP1
PCBP2
hnRNP C1/C2
C

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CONCLUSIONS
·
THE PI3K/AKT/MTOR PATHWAY IS FREQUENTLY ACTIVATED
IN MM
·
MTOR INHIBITORS PREVENT CAP-DEPENDENT
TRANSLATION OF CELL CYCLE PROTEINS IN MM CELLS
·
MTOR INHIBITORS INDUCE G1 ARREST IN MM CELLS
·
HIGH AKT ACTIVITY SENSITIZES TO MTOR INHIBITORS
·
HIGH AKT PREVENTS SALVAGE PATHWAY OF IRES-
MEDIATED, CAP-INDEPENDENT TRANSLATION
·
MTOR INHIBITORS CLINICALLY USEFUL IN DISEASE WITH
HIGH AKT ACTIVITY LIKE MM

---