HEMATOLOGICAL MALIGNANCIES SOLID TUMORS Multiple Myeloma Mantle Cell

HEMATOLOGICAL MALIGNANCIES SOLID TUMORS Multiple Myeloma Mantle Cell Lymphoma MALT Lymphoma Diffuse Large B-cell Lymphoma Hodgkin’s Lymphoma Myelodysplasic Syndrome Adult T-cell Leukemia (HTLV-1) Acute Lymphocytic Leukemia Acute Myeloid Leukemia Chronic Lymphocytic Leukemia Chronic Myeloid Leukemia NF- B Breast Cancer Cervical Cancer Prostate Cancer Renal Cancer Lung Cancer Colon Cancer Liver Cancer Pancreatic Cancer Esophageal Cancer Gastric Cancer Laryngeal Cancer Thyroid Cancer Parathyroid Cancer Melanoma Bladder Cancer Cylindroma Squamous Cell Carcinoma (Skin) Squamous Cell Carcinoma (Head and Neck) Oral Carcinoma Endometrial Carcinoma Ovarian Cancer Retinoblastoma Astrocytoma/Glioblastoma Figure 1 : Human cancers that have been linked to constitutive NF- B activation

Proliferation Inflammation Cyclin. D 1, Cyclin. E, CDK 2, c-MYC, TNF, IL 1, IL 6 TNF , IL 1, IL 8, MIP-2, MCP-1, i. NOS, COX 2, ICAM-1, E-Selectin Survival Cell death and anti-proliferative effects Fas. L, Fas and DR 4/5 p 53 p 21 WAF 1/CIP 1 NF- B Angiogenesis CXCL-1/8, IL-1/6, VEGF, IL 8, HIF-1 , TNF A 1/BFL 1, GADD 45 , Bcl-2, Bcl-XL, TRAF 1/2, XIAP, c. IAP 1/2, c-FLIP, A 20, IEX-1 L, Survivin, Telomerase, Mn. SOD Tumor promotion and Metastasis u. PA, MMP 2/9, VCAM-1, ICAM-1, ELAM-1, Kal-1, COX 2, i. NOS Figure 2: NF- B target genes involved in cancer development and progression

Classical NF- B Pathway CD 40 L BAFF TRAF 5/6 c-IAP 1 Alternative NF- B Pathway TRAF 5/6 TRAF 2 c-IAP 1 TRAF 3 c-IAP 2 NIK CYLD TAK 1 MLN IKK IKK BTZMB Rel. A p 105 Rel. A P P I B Rel. B p 100 p 50 P P Rel. B p 100 p 50 BTZMB p 100 processing p 105 processing Proteosomal degradation Rel. A p 50 Innate immunity Inflammation Cell survival Target genes Rel. B p 52 Rel. B p 50 Rel. B p 52 Target genes Lymphoid organogenesis B-cell maturation Humoral immunity Figure 3 : NF- B gain- and loss-of-function mutations in multiple myeloma

TNF- c-IAP 1 Ub c-IAP 2 TRAF 3 TRAF 2 NIK Ub Proteosomal degradation IKK IAP antagonists Caspase-3 XIAP IKK P P Rel. B Proteosomal degradation c-IAP 2 Proteosomal degradation IKK p 100 c-IAP 1 Ub Ub c-IAP 2 Caspase-8 TRAF 2 RIP 1 Ub c-IAP 1 Ub FADD TRADD IAP antagonists P P Rel. A Rel. B p 100 p 50 Caspase-7 P P I B p 50 p 100 processing Apoptosis Proteosomal degradation Rel. B p 50 Rel. B p 52 Rel. A p 50 Rel. B p 52 Target genes Apoptosis Target genes Bcl-x. L c-IAP 1/2 TRAF 1/2 Bcl-2 A 20 XIAP c-FLIP TNF- Figure 4: c. IAPs and IAP antagonists in the regulation of NF- B and cell death pathways