Biology and Pathology of Mantle Cell Lymphoma             Elias Campo  Hospital Clinic, University of Barcelona
Mantle Cell Lymphoma                                                                 1.0                                  ...
Improvement in Survival of Patients           with non-blastoid MCL                                    1996 to 2004       ...
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 PhenotypeCD20                   CD3       Cyclin D1             CD5
Prognostic Value of Proliferation in MCL                                 Ki-67        Ki-67                               ...
Cell Cycle Regulatory Pathways                Amplified (10%)           BMI-1                Deleted (30%)       ARF-INK4a...
Genetic Stability                                            DNA Damage Response Pathways                                 ...
Activated pathways in MCL without     apparent genetic alterationsWnt Pathway                                         PI3K...
Nucleus             stromal cells                                                                                         ...
Molecular Pathogenesis in MCL             Early                 Classical                  Blastoid  Naive B             M...
IGH Somatic Hypermutations in 807 MCL             Highly mutated                      111 (13%)             Minimally/bo...
MCL: From Naive to an Antigen Selected Cell ?                                                   UnMutated-MCL             ...
CD20CD5   CD3
Cyclin D1   p27
Cyclin D1 Negative MCL Variant                                            Cyclin D1              Cyclin D3         Cyclin ...
SOX11 mRNA Expression in non-HL       is Highly Specific of MCL                                           MCL             ...
Sox11 Protein Expression in MCL MCL                             Cyclin D1 (SP4)   Sox11CyclinD1 negative MCLMozos et al Ha...
SOX11 Expression is Highly Specific of MCL      and Recognizes Cyclin D1 Negative tumors Lymphoma                 Sox11 + ...
Classical MCL                Cyclin D1                  SOX11
CCND1               p27SOX11   SOX1
MCL with Indolent Clinical Behavior   OS from diagnosis   OS from treatment                             Martin P et al JCO...
Conventional vs Indolent MCL                     Clinical CharacteristicsClinical data                 Conventional       ...
iMCL and cMCL Have a Distinct Gene Expression Signature                                               Supervised analysis ...
SOX11 Protein Expression in MCL                  Cyclin D1           SOX11Indolent MCLConventional   MCL
Can SOX11 expression recognize a subtype of MCL with  different clinicopathological features and outcome? Clinical data   ...
Overall Survival in MCL patients according to SOX11 Expression                       1                                    ...
Cyclin D1
Cyclin D1   SOX11Cyclin D1   SOX11
“In situ” MCL (17 cases )•   Location at diagnosis     – Solitary LN                            10     – LN several sites ...
Genetically Stable                        Hypermutated IG                                       Leukemic/ non-nodal type M...
Conclusions-   MCL pathogenesis integrates alterations in cell cycle, DNA damage    response and survival pathways that ma...
AcknowledgmentsHospital Clínic-University      National Institute of Healthof Barcelona                    Bethesda       ...
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Dr. Campo MCL

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Dr. Campo MCL

  1. 1. Biology and Pathology of Mantle Cell Lymphoma Elias Campo Hospital Clinic, University of Barcelona
  2. 2. Mantle Cell Lymphoma 1.0 0.8 Probability 0.6 Cyclin D1 0.4 0.2 0.0 0 2 4 6 8 Years Complete Response 25% (6-50%)14 der(14) 11 der(11) Duration of CR 1.5 yrs (0.5-2.5 yrs) Median Survival 3-4 years IGH/CCND1
  3. 3. 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 Herrmann, A. et al. J Clin Oncol; 27:511-518 2009
  4. 4. MCL Pathogenesis • Cell Cycle Dysregulation • Dysruption of DNA damage response pathway • Cell survival pathways
  5. 5. Mantle Cell Lymphoma: Cytological Variants Classical Small cell Blastic Pleomorphic
  6. 6. MCL PhenotypeCD20 CD3 Cyclin D1 CD5
  7. 7. Prognostic Value of Proliferation in MCL Ki-67 Ki-67 MIPI-bKatzenberger, T. et al. Blood 2006;107:3407 Hoster, E. et al. Blood 2008;111:558-565
  8. 8. Cell Cycle Regulatory Pathways Amplified (10%) BMI-1 Deleted (30%) ARF-INK4a Locus 9 p14/p19arf p16ink4a Amplified (10%) MDM2 CDK4 / Cyclin DMutated (30%) p53 Rb Deleted (<5%) G1 S G2 M APOPTOSIS G1 S 17
  9. 9. Genetic Stability DNA Damage Response Pathways DNA damage Replication stress ATM 11 1.0 FS564stop R3008H R23stop 0.8 FS1349stop D2725V FS32stop No gain (n=8)PROBABILITY M1L K2717M 0.6 1 to 4 gains (n=28) ATM 0.4 protein p53 b-adaptin c-Abl Rad-3 PI3-kinase binding binding binding homology domain 0.2 >4 gains (n=6) P=0.02 0.0 0 2 4 6 8 10 Truncated protein Conserved residue YEARS substitution
  10. 10. Activated pathways in MCL without apparent genetic alterationsWnt Pathway PI3K, AKT, mTOR Pathway NFkB Pathway Navarro et al Sem Hematol 2011
  11. 11. Nucleus stromal cells nurse-like cells AbaDR4 folicullar dentritic cells AbaDR5 macrophages AbaCD38 TRAIL IL10 TNFa IL6 SDFa1 ImiDS VEGF CD31 CD40L TRAIL-R BCR AbaCD20 CD38 VEGF-R CD40T Lymph SrcK CXCR4 ImiDS CD20 IL-4 PK Inh PI3K Akt BAFF CD40L NF-KB Inh mTOR BAFF-R NF-KB CD40 PI3K/Akt/mTOR APRIL Axis Inh TACI Proteasome Inh BCL-2 Inh BCMA HSP90 Inhibitors IAPs Mitochondria HSP-90 DNMT/HDAC Inhibitors IAPs Antagonists Nucleoside Analogs Nucleus B cell neoplasm Saborit-Villarroya et al, Curr Drug Targets. 2010;11:769-80.
  12. 12. Molecular Pathogenesis in MCL Early Classical Blastoid Naive B MCL MCL MCLlymphocyte t(11;14) ATM p16/CDK4/Rb Bcl-2/other ARF/MdM2/p53Cyclin D1 CHK2 Increased High CellRb p27 Genomic Proliferation Survival Instability Jares P et al Nat Rev Cancer 2007
  13. 13. IGH Somatic Hypermutations in 807 MCL  Highly mutated 111 (13%)  Minimally/borderline mutated 458 (57%)  Truly Unmutated 238 (30%) Hadzidimitriou A et al Blood 2011
  14. 14. MCL: From Naive to an Antigen Selected Cell ? UnMutated-MCL T Cell-Independent Response Naïve Boderline Mutated-MCLV D J cμ cγ Antigen Selection Ig Somatic Mutations Class Switch HyperMutated-MCL
  15. 15. CD20CD5 CD3
  16. 16. Cyclin D1 p27
  17. 17. Cyclin D1 Negative MCL Variant Cyclin D1 Cyclin D3 Cyclin D2 Fu et al, Blood 2005
  18. 18. SOX11 mRNA Expression in non-HL is Highly Specific of MCL MCL CCND1- MCL, n=89 n=6 SOX11 CCND1BL, n=33 DLBCL, n=46 PMBL, n=20 FL, n=44 SOX11 CCND1 Mozos et al Haematologica 2009
  19. 19. Sox11 Protein Expression in MCL MCL Cyclin D1 (SP4) Sox11CyclinD1 negative MCLMozos et al Haematologica 2009
  20. 20. SOX11 Expression is Highly Specific of MCL and Recognizes Cyclin D1 Negative tumors Lymphoma Sox11 + Lymphoma Sox11 + MCL CCND1- 39/41 cHL 1/36 MCL 97/112 NLPHL 0/5 DLBCL 0/63 PTCL NOS 0/15 SMZL 0/9 AILT 0/5 MZL 0/11 Hepatosplenic 0/3 FL 0/22 ALK+ 0/3 CLL 0/12 ALK- 0/3 BL 2/8 (3)* T-PLL 2/3 B/T LBL 8/8 T/NK Nasal type 0/3Mozos A et al Haematologica 2009, updated * weak
  21. 21. Classical MCL Cyclin D1 SOX11
  22. 22. CCND1 p27SOX11 SOX1
  23. 23. MCL with Indolent Clinical Behavior OS from diagnosis OS from treatment Martin P et al JCO 2009
  24. 24. Conventional vs Indolent MCL Clinical CharacteristicsClinical data Conventional Indolent MCL (15) MCL (12)Chemotherapy 15 0Median 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
  25. 25. iMCL and cMCL Have a Distinct Gene Expression Signature Supervised analysis Indolent and conventional MCL LGALS3BP CSNK1E SOX11 KIAA1909 FARP1 PON2 CNN3 DBN1 HDGFRP3 CDK2AP1 HMGB3 SETMAR CNR1 RNGTTFernandez V et al Cancer Res 2010
  26. 26. SOX11 Protein Expression in MCL Cyclin D1 SOX11Indolent MCLConventional MCL
  27. 27. Can SOX11 expression recognize a subtype of MCL with different clinicopathological features and outcome? Clinical data SOX11 - SOX11 + (n = 15) (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
  28. 28. Overall Survival in MCL patients according to SOX11 Expression 1 SOX11 negative (N=15; dead: 4) .8 .6 Sox11 - .4 PROBABILITY SOX11 positive (N=97; dead: 68) .2 Sox11 + 0 0 2 4 6 8 10 12 14 16 YEARS P< 0.001 Fernandez V et al Cancer Res 2010
  29. 29. Cyclin D1
  30. 30. Cyclin D1 SOX11Cyclin D1 SOX11
  31. 31. “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
  32. 32. Genetically Stable Hypermutated IG Leukemic/ non-nodal type MCL (del)17p “In situ” MCL SOX11-t(11;14) SOX11+ Classical MCL Blastoid MCL Genomic Instability Unmutated Ig
  33. 33. 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.
  34. 34. AcknowledgmentsHospital Clínic-University National Institute of Healthof Barcelona Bethesda Adrian WiestnerSilvia Bea Wyndham WilsonCristina Royo Elaine JaffeAlba NavarroGuillem ClotAlejandra Martinez Institute of Pathology-WürzburgEva Giné Elena HartmannGonzalo Gutierrez Andreas RosenwaldVerònica FernàndezDolors Colomer Abteilung für Klinische-Pathologie-Neus Villamor StuttgartPedro Jares German OttArmando Lopez-GuillermoUniversity HospitalSchleswig-Holstein-KielChistiane Pott Addenbrooke’s Hospital-CambridgeItziar Salverria Nicola TrimReiner Siebert Wendy ErberUniversity Hospital Munich-Grosshadern-Munich S. Orsola-Malpighi Hospital-BolognaMartin Dreyling Claudio Agostinelli Stefano A Pileri
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