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Elias Campo
Hospital Clinic, University of Barcelona
Biology and Pathology of
Mantle Cell Lymphoma
Mantle Cell Lymphoma
14 der(14) 11 der(11)
IGH/CCND1
Years
Pro
bability
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8
Complete Response 25% (6-50%)
Duration of CR 1.5 yrs (0.5-2.5 yrs)
Median Survival 3-4 years
Cyclin D1
Herrmann, A. et al. J Clin Oncol; 27:511-518 2009
Improvement in Survival of Patients
with non-blastoid MCL
1996 to 2004
1975 to 1986
• New diagnostic tools and management measures
• Application of new therapeutic regimens
MCL Pathogenesis
• Cell Cycle Dysregulation
• Dysruption of DNA damage
response pathway
• Cell survival pathways
Mantle Cell Lymphoma: Cytological Variants
Classical Small cell
Blastic Pleomorphic
MCL Phenotype
CD20
Cyclin D1 CD5
CD3
Prognostic Value of Proliferation in MCL
Ki-67 Ki-67
MIPI-b
Hoster, E. et al. Blood 2008;111:558-565 Katzenberger, T. et al. Blood 2006;107:3407
ARF-INK4a Locus
p16ink4a
CDK4 / Cyclin D
Rb
p14/p19arf
MDM2
p53
BMI-1
Cell Cycle Regulatory Pathways
G1 S G2 M APOPTOSIS G1 S
Mutated (30%)
Amplified (10%)
Amplified (10%)
Deleted (30%)
9
17
Deleted (<5%)
DNA Damage Response Pathways
ATM
DNA damage Replication
stress
11
ATM
protein
R23stop
FS32stop
M1L
R3008H
D2725V
K2717M
FS564stop
FS1349stop
p53
binding
c-Abl
binding
b-adaptin
binding
PI3-kinase
domain Rad-3
homology
Truncated protein Conserved residue
substitution
Genetic Stability
YEARS
PR
OB
AB
ILIT
Y
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10
No gain (n=8)
1 to 4 gains (n=28)
>4 gains (n=6)
P=0.02
Activated pathways in MCL without
apparent genetic alterations
Wnt Pathway
PI3K, AKT, mTOR
Pathway
NFkB Pathway
Navarro et al Sem Hematol 2011
Proteasome Inh
CD20
CD40L
CD40
CD40L
CD40
TRAIL-R
TRAIL
AbaDR4
AbaDR5
CXCR4
SDFa1
PI3K
Akt
mTOR
NF-KB
BCL-2 Inh
IAPs
Antagonists
IL6 TNFa
IAPs
PI3K/Akt/mTOR
Axis Inh
NF-KB Inh
Mitochondria
stromal cells
nurse-like cells
folicullar dentritic cells
macrophages
Nucleus
IL-4
Nucleus
B cell neoplasm
BAFF
APRIL
TACI
BCMA
HSP-90
HSP90
Inhibitors
SrcK
CD38
CD31
BCR
BAFF-R
PK Inh
AbaCD20
AbaCD38
T Lymph
VEGF
VEGF-R
ImiDS
IL10 ImiDS
DNMT/HDAC
Inhibitors
Nucleoside
Analogs
Saborit-Villarroya et al, Curr Drug Targets. 2010;11:769-80.
Naive B
lymphocyte
Increased
Genomic
Instability
ATM
CHK2
Early
MCL
Classical
MCL
t(11;14)
Cyclin D1
Rb p27
Molecular Pathogenesis in MCL
Blastoid
MCL
p16/CDK4/Rb
ARF/MdM2/p53
High
Proliferation
Bcl-2/other
Cell
Survival
Jares P et al Nat Rev Cancer 2007
IGH Somatic Hypermutations in 807 MCL
Hadzidimitriou A et al Blood 2011
Highly mutated 111 (13%)
Minimally/borderline mutated 458 (57%)
Truly Unmutated 238 (30%)
MCL: From Naive to an Antigen Selected Cell ?
Antigen Selection
Ig Somatic Mutations
Class Switch
Naïve
V D J cμ cγ
T Cell-Independent Response
HyperMutated-MCL
UnMutated-MCL
Boderline Mutated-MCL
CD5 CD3
CD20
Cyclin D1 p27
Cyclin D1 Negative MCL Variant
Cyclin D1
Cyclin D3 Cyclin D2
Fu et al, Blood 2005
MCL, n=89
MCL
CCND1-
n=6
SOX11
CCND1
SOX11
CCND1
BL, n=33 DLBCL, n=46 PMBL, n=20 FL, n=44
SOX11 mRNA Expression in non-HL
is Highly Specific of MCL
Mozos et al Haematologica 2009
CyclinD1 negative MCL
MCL Cyclin D1 (SP4) Sox11
Sox11 Protein Expression in MCL
Mozos et al Haematologica 2009
SOX11 Expression is Highly Specific of MCL
and Recognizes Cyclin D1 Negative tumors
* weak
Lymphoma Sox11 +
MCL CCND1- 39/41
MCL 97/112
DLBCL 0/63
SMZL 0/9
MZL 0/11
FL 0/22
CLL 0/12
BL 2/8 (3)*
B/T LBL 8/8
Lymphoma Sox11 +
cHL 1/36
NLPHL 0/5
PTCL NOS 0/15
AILT 0/5
Hepatosplenic 0/3
ALK+ 0/3
ALK- 0/3
T-PLL 2/3
T/NK Nasal type 0/3
Mozos A et al Haematologica 2009, updated
SOX11
Cyclin D1
Classical MCL
CCND1
SOX11 SOX1
1
p27
MCL with Indolent Clinical Behavior
OS from diagnosis OS from treatment
Martin P et al JCO 2009
Conventional vs Indolent MCL Clinical Characteristics
Clinical data Conventional
MCL (15)
Indolent
MCL (12)
Chemotherapy 15 0
Median Follow-up 15 m (0.5 - 79) 70 m (25-121)
5-year Overall Survival 49% 100%*
ECOG≥2 70% 0+
Intermediate/High MIPI 46% 0+
Lymphadenopathy (>1cm) 15/15 2/12+
Lymphocytosis (≥5x109/L) 9/11 4/9
+ p <0.05
* p=0.002 Fernandez V et al Cancer Res 2010
SETMAR HMGB3
FARP1
HDGFRP3
DBN1
PON2
CNN3
SOX11 KIAA1909
RNGTT
CNR1
CDK2AP1
CSNK1E LGALS3BP
Supervised analysis
Indolent and
conventional MCL
iMCL and cMCL Have a Distinct Gene Expression Signature
Fernandez V et al Cancer Res 2010
SOX11 Cyclin D1
Conventional
MCL
Indolent MCL
SOX11 Protein Expression in MCL
Can SOX11 expression recognize a subtype of MCL with
different clinicopathological features and outcome?
Clinical data SOX11 -
(n = 15)
SOX11 +
(n = 97)
High MIPI 33% 46%
Lymphn nodes (>1cm) 53% 99% *
Splenomegaly 92% 48%*
WBC ≥ 10x109/L 57% 18%*
Lymphocytosis (≥5x109/L) 83% 24% *
Ki67 high >50% 20% 28%
Adriamycin-Regimens 67% 72%
Complete Response 40% 54%
5-year OS (%) 78% 36%*
+ p <0.01 Fernandez V et al Cancer Res 2010
Overall Survival in MCL patients according to SOX11 Expression
Sox11 -
Sox11 +
P< 0.001
0 2 4 6 8 10 12 14 16
YEARS
0
.2
.4
.6
.8
1
PR
OB
AB
ILIT
Y
SOX11 negative (N=15; dead: 4)
SOX11 positive (N=97; dead: 68)
Fernandez V et al Cancer Res 2010
Cyclin D1
Cyclin D1 SOX11
Cyclin D1 SOX11
“In situ” MCL (17 cases )
• Location at diagnosis
– Solitary LN 10
– LN several sites 2
– Extranodal 5
– Bone Marrow, Peripheral blood 3/7
• SOX11+ 7/16 (44%)
• Follow-up
– 9 W&W
• 2 Progression to overt MCL (4 years)
• 4 Alive with stable (2) or no disease (2) (med 8 yr; range 1-19)
• 1 Dead, unrelated cause (1.4 y, 84 year-old)
– 4 Chemotherapy Alive No Disease 4 yr
– 2 Rx Alive no Disease > 2 yr
• 1 incidental finding 3 yr after overt MCL in complete remission
Carvajal-Cuenca et al Haematologica 2011
Classical MCL
t(11;14)
Blastoid MCL
Genomic Instability
Unmutated Ig
Leukemic/ non-nodal type MCL
Genetically Stable
Hypermutated IG
(del)17p
“In situ” MCL
SOX11-
SOX11+
Conclusions
- MCL pathogenesis integrates alterations in cell cycle, DNA damage
response and survival pathways that may be targeted by new
therapies
- Antigen selection may play a role in the pathogenesis of at least a
subgroup of MCL
- Cyclin D1 negative MCL can be recognized by SOX11 expression
and seem to have similar clinical and genetic characteristics to
conventional MCL.
- Some MCL have an indolent clinical course and may benefit of a
more conservative clinical management. A subset of them seems to
correspond to a different biological subtype.
- We may recognize early steps in MCL lymphomagenesis that
should be managed with caution.
Acknowledgments
Hospital Clínic-University
of Barcelona
Silvia Bea
Cristina Royo
Alba Navarro
Guillem Clot
Alejandra Martinez
Eva Giné
Gonzalo Gutierrez
Verònica Fernàndez
Dolors Colomer
Neus Villamor
Pedro Jares
Armando Lopez-Guillermo
S. Orsola-Malpighi Hospital-Bologna
Claudio Agostinelli
Stefano A Pileri
Addenbrooke’s Hospital-Cambridge
Nicola Trim
Wendy Erber
University Hospital
Schleswig-Holstein-Kiel
Chistiane Pott
Itziar Salverria Reiner Siebert University Hospital Munich-Grosshadern-Munich
Martin Dreyling
National Institute of Health
Bethesda
Adrian Wiestner
Wyndham Wilson
Elaine Jaffe
Institute of Pathology-Würzburg
Elena Hartmann
Andreas Rosenwald
Abteilung für Klinische-Pathologie-
Stuttgart
German Ott