Location of Repository

The mechanism of action of novel therapies for use in Chronic Lymphocytic Leukaemia

By Susan Louise Kohlhaas


Chronic Lymphocytic Leukaemia (CLL) remains incurable and novel treatments are urgently required to combat this disease. The proteasome inhibitor bortezomib induces high levels of apoptosis in vitro in CLL patient samples, but clinical trials have been discouraging. In this study, bortezomib induced apoptosis in all CLL samples tested at nanomolar concentrations. However, incubation of CLL cells with red blood cells (RBCs) reduced the activity of bortezomib. These data imply that RBC uptake may reduce the activity of bortezomib in vivo.\ud TNF-related apoptosis inducing ligand (TRAIL) is an attractive cancer therapy because of its selectivity towards tumour cells. TRAIL and agonistic mAbs to two TRAIL receptors (TRAIL-R1 and TRAIL-R2) are in clinical trials. CLL cells are resistant to TRAIL but can be sensitised by pre-treatment with histone deacetylase inhibitors (HDACi). HDACi sensitised CLL cells to preparations of TRAIL that induce apoptosis through TRAIL-RI but not through TRAIL-R2. In contrast, K562 cells, when pre-treated with HDACi, responded to preparations of TRAIL that induce apoptosis through TRAIL-R2. To confirm this, TRAIL receptor-selective mutants were generated and tested for specificity in cell lines. CLL cells, pre-treated with depsipeptide, responded only to the TRAIL-R1 mutant. These data confirm that CLL cells can be sensitised to TRAIL induced apoptosis primarily through TRAIL-R1 and that clinical trials in CLL should focus on HDACi in combination with preparations of TRAIL that induce apoptosis through TRAIL-R1.\ud Recent publications suggest that internalisation of CD95 and TNFRI are required for induction of apoptosis. TRAIL-internalisation has not been widely studied. In this study, TRAIL-induced DISC formation was shown to occur at the plasma membrane, suggesting that TRAIL signalling is unlike other members of the TNF superfamily (CD95L and TNFa). Inhibiting TRAIL internalisation with hyperosmotic solution did not inhibit apoptosis induction, suggesting that internalisation is not important for TRAIL activity

Publisher: University of Leicester
Year: 2007
OAI identifier: oai:lra.le.ac.uk:2381/9226

Suggested articles



  1. (2000). A domain in TNF receptors that mediates ligandindependent receptor assembly and signaling. "
  2. (1981). A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. "
  3. (1995). A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. "
  4. (2006). A novel endocytic mechanism of epidermal growth factor receptor sequestration and internalization. "
  5. (2005). A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. "
  6. (2006). A novel proteasome inhibitor NPI-0052 as an anticancer therapy. "
  7. (1988). A phase I trial of intravenously-administered recombinant tumor necrosis factor-alpha in cancer patients. "
  8. (2002). A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. "
  9. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. "
  10. (2000). A unique zinc-binding site revealed by a high-resolution X-ray structure of homotrimeric Apo2L/TRAIL. "
  11. (2003). Activation and suppression of the TRAIL deathreceptor pathway in chemotherapy sensitive and resistant follicular lymphoma cells. "
  12. (2005). Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-RI and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicinand bortezomib-induced cell death. "
  13. (2003). Albumin activates the AKT signaling pathway and protects B-chronic lymphocytic leukemia cells from chlorambuciland radiation-induced apoptosis. "
  14. (1997). Amplification of multiple regions of chromosome 12, including 12g13-15, in chronic lymphocytic leukaemia. "
  15. (1997). An antagonist decoy receptor and a death domain-containing receptor for TRAIL. "
  16. (1999). An APAF-1. cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. "
  17. (1975). An EBV-genome-negative cell line established from an American Burkitt lymphoma; receptor characteristics. EBV infectibility and permanent conversion into EBV-positive sublines by in vitro infection. "
  18. (2006). An electrodiagnostic evaluation of the effect of pre-existing peripheral nervous system disorders in patients treated with the novel proteasome inhibitor bortezomib. "
  19. (2002). An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis. "
  20. (2005). Analysis of the efficacy and toxicity of bortezomib for treatment of relapsed or refractory multiple myeloma in community practice. "
  21. (2002). And all of a sudden it's over: mitochondrial outer-membrane permeabilization in apoptosis. "
  22. (2006). Anticancer activities of histone deacetylase inhibitors. "
  23. (2006). Anticancer agents sensitize osteosarcoma cells to TNF-related apoptosis-inducing ligand downmodulating IAP family proteins. "
  24. (2000). Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. "
  25. (1999). Apoptosis control by death and decoy receptors. "
  26. (2000). Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. "
  27. (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. "
  28. (2005). Apoptotic pathways: ten minutes to dead. "
  29. (2002). Autologous and allogeneic stem cell transplantation for chronic lymphocytic leukemia. "
  30. (1999). B-cell chronic lymphocytic leukemia: a bird of a different feather. "
  31. (1993). bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia. "
  32. (2005). Bik/NBK accumulation correlates with apoptosisinduction by bortezomib (PS-341, Velcade) and other proteasome inhibitors. "
  33. (2006). Bim plays a crucial role in synergistic induction of apoptosis by the histone deacetylase inhibitor SBHA and TRAIL in melanoma cells. "
  34. (2000). Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cellderived factor-1. "
  35. (2005). Bodyguards and assassins: Bcl-2 family proteins and apoptosis control in chronic lymphocytic leukaemia. "
  36. (2006). Bortezomib for multiple myeloma. "
  37. (2005). Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. "
  38. (2005). Bortezomib-induced Sweet syndrome. "
  39. (2005). Bortezomib-induced Sweet's syndrome. " Haematologica 90(12 Suppl):
  40. (2005). Bortezomib, a novel proteasome inhibitor, in the treatment of hematologic malignancies. "
  41. (2006). Bortezomib: efficacy comparisons in solid tumors and hematologic malignancies. "
  42. (2006). Bortezomib: proteasome inhibition as an effective anticancer therapy. "
  43. (2002). c-FLIP(L) is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis. "
  44. (2006). Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. "
  45. (1999). Caspase activation involves the formation of the aposome, a large (approximately 700 kDa) caspase-activating complex. "
  46. (1999). Caspase structure, proteolytic substrates, and function during apoptotic cell death. "
  47. (2003). Caspase-activation pathways in apoptosis and immunity. "
  48. (1997). Casper is a FADD- and caspase-related inducer of apoptosis. "
  49. (2004). CDDO induces apoptosis via the intrinsic pathway in lymphoid cells. "
  50. (1972). Cellular events in the adrenal cortex following ACTH deprivation. "
  51. (2002). Chapter 2: Materials and Methods Chapter 2: Materials and Methods Chapter 2: Materials and Methods
  52. (2005). Chronic lymphocytic leukemia. "
  53. (2004). Clathrin-dependent endocytosis. "
  54. (2005). Clathrin-independent endocytosis of ubiquitinated cargos. "
  55. (2005). Clathrin-independent endocytosis: new insights into caveolae and non-caveolar lipid raft carriers. "
  56. (2005). Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma. "
  57. (1988). Clinical pharmacokinetics of valproic acid--1988. "
  58. (2003). Clinical pharmacology of flavopiridol following a 72-hour continuous infusion. "
  59. (1997). Cloning and characterization of TRAILR3, a novel member of the emerging TRAIL receptor family. "
  60. (2006). Cohen Shortlisted for the CLL Forum Young Investigators Prize,
  61. (2004). Compartmentalization of TNF receptor 1 signaling: internalized TNF receptosomes as death signaling vesicles. "
  62. (2003). Conformational change and mitochondrial translocation of Bax accompany proteasome inhibitor-induced apoptosis of chronic lymphocytic leukemic cells. "
  63. (2003). Control of apoptosis in the immune system: Bcl-2, BH3-only proteins and more. "
  64. (1997). Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. "
  65. (2003). Cycling B-CLL cells are highly susceptible to inhibition of the proteasome: involvement of p27, early D-type cyclins, Bax, and caspase-dependent and -independent pathways. "
  66. (1997). Cytochrome c and dATP-dependent formation of Apaf1 /caspase-9 complex initiates an apoptotic protease cascade. "
  67. (1999). Cytotoxicity induced by the combination of valproic acid and tumor necrosis factor-alpha: implication for valproic acidassociated hepatotoxicity syndrome. "
  68. (1995). Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. "
  69. (2006). Death-receptor activation halts clathrindependent endocytosis. "
  70. (2006). Debatin
  71. (1998). Deficiency of the ATM protein expression defines an aggressive subgroup of B-cell chronic lymphocytic leukemia. "
  72. (2005). Depsipeptide (FR901228) enhances the cytotoxic activity of TRAIL by redistributing TRAIL receptor to membrane lipid rafts. "
  73. (2006). Deregulated NF-kappaB activity in haematological malignancies. "
  74. (2000). Deregulation of the ubiquitin system and p53 proteolysis modify the apoptotic response in B-CLL lymphocytes. "
  75. (2006). Designed tumor necrosis factor-related apoptosis-inducing ligand variants initiating apoptosis exclusively via the DR5 receptor. "
  76. (2004). Development of the proteasome inhibitor Velcade (Bortezomib). "
  77. (2001). Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. "
  78. (1996). Differential inhibition of calpain and proteasome activities by peptidyl aldehydes of di-leucine and tri-leucine. "
  79. (1999). Differential modulation of apoptosis sensitivity in CD95 type I and type II cells. "
  80. (2004). Direct binding of Fas-associated death domain (FADD) to the tumor necrosis factor-related apoptosis-inducing ligand receptor DRS is regulated by the death effector domain of FADD. "
  81. (1985). Distinctions between endemic and sporadic forms of Epstein-Barr virus-positive Burkitt's lymphoma. "
  82. (2002). Distinctive features of "nurselike" cells that differentiate in the context of chronic lymphocytic leukemia. "
  83. (2005). Does CD95 have tumor promoting activities? "
  84. (2004). Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2IJTRAIL-induced apoptosis. "
  85. (2003). Dynamics of endosomal sorting.
  86. (2005). Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. "
  87. (1968). Effects of temperature, potassium, and calcium on the electrical potential difference in HeLa cells. "
  88. (2003). Effects of the proteasome inhibitor, bortezomib, on apoptosis in isolated lymphocytes obtained from patients with chronic lymphocytic leukemia. "
  89. (2005). Efficient TRAIL-RI/DR4-mediated apoptosis in melanoma cells by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). "
  90. (2004). Emerging non-apoptotic functions of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L. "
  91. (2006). Endocytosis conducts the cell signaling orchestra. "
  92. (1985). Environmental factors and leukaemia. "
  93. (1975). Establishment and characterization of an EpsteinBarr virus (EBC)-negative lymphoblastoid B cell line (BJA-B) from an exceptional, EBV-genome-negative African Burkitt's lymphoma. "
  94. (2002). Expression of TRAIL and TRAIL receptors in colon carcinoma: TRAIL-RI is an independent prognostic parameter. "
  95. (2000). FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. "
  96. (2000). Familial chronic lymphocytic leukaemia: a survey and review of published studies. "
  97. (2006). Familial chronic lymphocytic leukemia. "
  98. (1997). FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis. "
  99. (2005). Flavopiridol administered as a 24-hour continuous infusion in chronic lymphocytic leukemia lacks clinical activity. "
  100. (1996). FLICE, a novel FADD-homologous ICE/CED-3 -like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. "
  101. (2006). Flotillin-1 defines a clathrin-independent endocytic pathway in mammalian cells. "
  102. (2006). Fludarabine in chronic lymphocytic leukaemia. "
  103. (2003). For whom the bell tolls: protein quality control of the endoplasmic reticulum and the ubiquitin-proteasome connection. "
  104. (2006). Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. "
  105. (1999). Functional analysis of TRAIL receptors using monoclonal antibodies. "
  106. (1998). Generation of coated intermediates of clathrinmediated endocytosis on protein-free liposomes. "
  107. (2000). Genomic aberrations and survival in chronic lymphocytic leukemia. "
  108. (2005). Good prognosis cytogenetics in B-cell chronic lymphocytic leukemia is associated in vitro with low susceptibility to apoptosis and enhanced immunogenicity. "
  109. (1995). Growth factors can protect B-chronic lymphocytic leukaemia cells against programmed cell death without stimulating proliferation. "
  110. (2005). HGS-ETRI, a fully human TRAIL-receptor monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo. "
  111. (2004). Histone deacetylase inhibitors potentiate TNFrelated apoptosis-inducing ligand (TRAIL)-induced apoptosis in lymphoid malignancies. "
  112. (1996). Human bone marrow stromal cells prevent apoptosis and support the survival of chronic lymphocytic leukaemia cells in vitro. "
  113. (2004). Human normal hepatocytes are susceptible to apoptosis signal mediated by both TRAIL-RI and TRAIL-R2. "
  114. (1997). I-FLICE, a novel inhibitor of tumor necrosis factor receptor-l- and CD-95-induced apoptosis. "
  115. (1995). Identification and characterization of a new member of the TNF family that induces apoptosis. "
  116. (1997). Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL. "
  117. (2006). If the prophet does not come to the mountain: dynamics of signaling complexes in NF-kappaB activation. "
  118. (1999). Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. "
  119. (2005). IKK/NF-kappaB signaling: balancing life and death--a new approach to cancer therapy. "
  120. (2005). Images in clinical Medicine. Bortezomibinduced skin lesions. "
  121. (2006). Imperfect correlation between p53 dysfunction and deletion of TP53 and ATM in chronic lymphocytic leukaemia. "
  122. (1999). Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. "
  123. (1996). Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. "
  124. (2005). Induction of apoptosis by proteasome inhibitors in B-CLL cells is associated with downregulation of CD23 and inactivation of Notch2. "
  125. (2004). Induction of cell cycle arrest and apoptosis by the proteasome inhibitor PS-341 in Hodgkin disease cell lines is independent of inhibitor of nuclear factor-kappaB mutations or activation of the CD30, CD40, and RANK receptors. "
  126. (1994). Induction of mutant dynamin specifically blocks endocytic coated vesicle formation. "
  127. (2006). Inhibition of bortezomib-induced apoptosis by red blood cell uptake. "
  128. (2006). Inhibition of Bortezomib-induced Apoptosis induction in Chronic Lymphocytic Leukemia by Red Blood Cell uptake" Abstract and poster presentation at the 5`h
  129. (1997). Inhibition of death receptor signals by cellular FLIP. "
  130. (2006). Inhibition of histone deacetylase class I but not class II is critical for the sensitization of leukemic cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. "
  131. (1998). Inhibition of nuclear factor kappaB activation attenuates apoptosis resistance in lymphoid cells. "
  132. (1999). Inhibition of the receptor-binding function of clathrin adaptor protein AP-2 by dominant-negative mutant mu2 subunit and its effects on endocytosis. "
  133. (2005). Interactive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells: involvement of both death receptor and mitochondrial pathways. "
  134. (2006). Involvement of caspase-2 and caspase-9 in endoplasmic reticulum stress-induced apoptosis: a role for the IAPs. "
  135. (2004). Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. "
  136. (1996). Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. "
  137. (2002). Is chronic lymphocytic leukemia one disease? "
  138. (1993). Lethal effect of the anti-Fas antibody in mice. "
  139. (2005). Life in the balance: how B113-only proteins induce apoptosis. "
  140. (2006). Life-threatening motor neurotoxicity in association with bortezomib. "
  141. (2006). Lipid rafts: now you see them, now you don't. "
  142. (1977). Lozzio
  143. (2005). Marked clinical activity of the proteasome inhibitor bortezomib in patients with follicular and mantle-cell lymphoma. "
  144. (2004). Maximal apoptosis of renal cell carcinoma by the proteasome inhibitor bortezomib is nuclear factor-kappaB dependent. "
  145. (2004). MCL-1 promoter insertions dial-up aggressiveness of chronic leukemia.
  146. (2006). Mcl-1L cleavage is involved in TRAIL-RIand TRAIL-R2-mediated apoptosis induced by HGS-ETR1 and HGS-ETR2 human mAbs in myeloma cells. "
  147. (2006). Mechanical aspects of apoptosome assembly. "
  148. (2002). Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukaemia. "
  149. (2006). Membrane microdomains, caveolae, and caveolar endocytosis of sphingolipids. "
  150. (2001). Modulation of tumor necrosis factor apoptosisinducing ligand- induced NF-kappa B activation by inhibition of apical caspases. "
  151. (2005). Molecular determinants of kinase pathway activation by Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand. "
  152. (2001). Molecular mechanisms of death-receptor-mediated apoptosis. "
  153. (2002). Molecular ordering of the initial signaling events of CD95. "
  154. (2003). Monoclonal antibody therapeutics and apoptosis. "
  155. (2006). Monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) induces apoptosis in primary renal cell carcinoma cells in vitro and inhibits tumor growth in vivo. "
  156. (1997). MRIT, a novel death-effector domaincontaining protein, interacts with caspases and Bc1XL and initiates cell death. "
  157. (2002). Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. "
  158. (2005). Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL. "
  159. (2001). Mutations of tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-RI) and receptor 2 (TRAIL-R2) genes in metastatic breast cancers. "
  160. (1998). Neuroendocrine synaptic vesicles are formed in vitro by both clathrin-dependent and clathrin-independent pathways. "
  161. (2006). NF-kappaB in solid tumors. "
  162. (2001). Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. "
  163. (1999). Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2,
  164. (2002). Origin, originality, functions, subversions and molecular signalling of macropinocytosis. "
  165. (2005). Pathogenesis of mantle-cell lymphoma: all oncogenic roads lead to dysregulation of cell cycle and DNA damage response pathways. "
  166. (2005). Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. "
  167. (2005). Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. "
  168. (2006). Phase II study of single-agent bortezomib for the treatment of patients with fludarabine-refractory B-cell chronic lymphocytic leukemia. "
  169. (2001). Potential and caveats of TRAIL in cancer therapy. "
  170. (2006). Preclinical differentiation between apparently safe and potentially hepatotoxic applications of TRAIL either alone or in combination with chemotherapeutic drugs. "
  171. (2001). Preclinical studies to predict the disposition of Apo2litumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety. "
  172. (2005). Preligand assembly domain-mediated ligandindependent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis. "
  173. (2005). Proapoptotic Bak is sequestered by Mcl-1 and BclxL, but not Bcl-2, until displaced by BH3-only proteins. " Genes Dev
  174. (1987). Prognostic factors in chronic lymphocytic leukemia. "
  175. (1994). Proliferation centres in B-cell malignant lymphoma, lymphocytic (B-CLL): an immunophenotypic study. "
  176. (2006). Proteasome inhibition as a new therapeutic principle in hematological malignancies. "
  177. (2006). Proteasome inhibitor bortezomib for the treatment of multiple myeloma. "
  178. (2006). Proteasome inhibitor induces apoptosis through induction of endoplasmic reticulum stress. "
  179. (2006). Proteasome inhibitor PS-341 induces apoptosis in cisplatin-resistant squamous cell carcinoma cells by induction of Noxa. "
  180. (2004). Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells. "
  181. (2001). Proteasome inhibitor-induced apoptosis of Bchronic lymphocytic leukaemia cells involves cytochrome c release and caspase activation, accompanied by formation of an approximately 700 kDa Apaf-1 containing apoptosome complex. "
  182. (2006). Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. "
  183. (1998). Proteasome inhibitors induce apoptosis in glucocorticoid-resistant chronic lymphocytic leukemic lymphocytes. "
  184. (2005). Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells. "
  185. (1999). Proteasome inhibitors: a novel class of potent and effective . antitumor agents.
  186. (2002). Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1. "
  187. (2007). Publications arising from this
  188. (1998). Rare loss-of-function mutation of a death receptor gene in head and neck cancer. "
  189. (2005). Receptor-selective mutants of apoptosis-inducing ligand 2/tumor necrosis factor-related apoptosis-inducing ligand reveal a greater contribution of death receptor (DR) 5 than DR4 to apoptosis signaling. "
  190. (2003). Regulation of proliferation, survival and apoptosis by members of the TNF superfamily. "
  191. (2005). Regulatory mechanisms of dynamin-dependent endocytosis.
  192. (2001). Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. "
  193. (2005). Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. "
  194. (2003). Role of the TRAIL/APO2-L death receptors in chlorambucil- and fludarabine-induced apoptosis in chronic lymphocytic leukemia. "
  195. (2006). Routine clinical use of alemtuzumab in patients with heavily pretreated B-cell chronic lymphocytic leukemia: a nation-wide retrospective study in Austria. "
  196. (1999). Safety and antitumor activity of recombinant soluble Apo2 ligand. "
  197. (2005). Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma. "
  198. (2004). Sensitization of mesothelioma to TRAIL apoptosis by inhibition of histone deacetylase: role of Bcl-xL down-regulation. "
  199. (2005). Severe irreversible bilateral hearing loss after bortezomib (VELCADE) therapy in a multiple myeloma (MM) patient. "
  200. (2006). Severe pulmonary complications in Japanese patients after bortezomib treatment for refractory multiple myeloma. "
  201. (2006). Severe reversible cardiac failure after bortezomib treatment combined with chemotherapy in a non-small cell lung cancer patient: a case report. "
  202. (2005). Side effects and good effects from new chemotherapeutic agents. Case 3. Bortezomib in primary refractory plasmacytoma. "
  203. (1996). Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95. "
  204. (2005). Skin lesions induced by bortezomib. "
  205. (2002). Spontaneous and drug-induced apoptosis is mediated by conformational changes of Bax and Bak in B-cell chronic lymphocytic leukemia. "
  206. (1989). Spontaneous programmed death (apoptosis) of B-chronic lymphocytic leukaemia cells following their culture in vitro. "
  207. (2004). Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway. "
  208. (1997). T LICE is activated by association with the CD95 death-inducing signaling complex (DISC). "
  209. (2000). Temperature-sensitive differential affinity of TRAIL for its receptors. DRS is the highest affinity receptor. "
  210. (1993). The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. "
  211. (2006). The clinical trail of TRAIL. "
  212. (2004). The development of proteasome inhibitors as anticancer drugs. "
  213. (2006). The histone deacetylase inhibitor, suberoylanilide hydroxamic acid, overcomes resistance of human breast cancer cells to Apo2L/TRAIL. "
  214. (2005). The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. "
  215. (1999). The prognostic significance of 13g14 deletions in chronic lymphocytic leukemia. "
  216. (2006). The proteasome inhibitor bortezomib induces apoptosis in mantle-cell lymphoma through generation of ROS and Noxa activation independent of p53 status. "
  217. (2005). The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via 1313-only proteins Bik and Bim. "
  218. (2006). The proteasome inhibitor NPI-0052 is a more effective inducer of apoptosis than bortezomib in lymphocytes from patients with chronic lymphocytic leukemia. "
  219. (2002). The proteasome: a novel target for cancer chemotherapy. "
  220. (2004). The proteasome: a suitable antineoplastic target. "
  221. (2003). The proteasome: structure, function, and role in the cell. "
  222. (2004). The protein structures that shape caspase activity, specificity, activation and inhibition. "
  223. (1997). The receptor for the cytotoxic ligand TRAIL. "
  224. (1998). The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. "
  225. (2006). The role of receptor internalization in CD95 signaling. "
  226. (1984). The role of T3 surface molecules in the activation of human T cells: a two-stimulus requirement for IL 2 production reflects events occurring at a pre-translational level. "
  227. (2005). The roles of receptor and ligand endocytosis in regulating Notch signaling. "
  228. (2006). The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells. "
  229. (2003). The ubiquitin proteolytic system and pathogenesis of human diseases: a novel platform for mechanism-based drug targeting. "
  230. (1999). The ubiquitin-proteasome pathway and pathogenesis of human diseases. "
  231. (2002). The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. "
  232. (2003). TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-kappaB. "
  233. (2005). TRAIL receptor-selective mutants signal to apoptosis via TRAIL-RI in primary lymphoid malignancies. "
  234. (2003). TRAIL-R2 (DR5) mediates apoptosis of synovial fibroblasts in rheumatoid arthritis. "
  235. (1997). TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. "
  236. (2004). Treatment of human chronic lymphocytic leukemia cells with the proteasome inhibitor bortezomib promotes apoptosis. "
  237. (1999). Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5. "
  238. (1997). Trilineage hematopoietic toxicity associated with valproic acid therapy. "
  239. (2005). Tumor lysis syndrome after bortezomib therapy for plasma cell leukemia. "
  240. (1999). Tumor necrosis factor receptor and Fas signaling mechanisms. "
  241. (2002). Tumor-cell resistance to death receptor--induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. "
  242. (1999). Tumoricidal activity of tumor necrosis factorrelated apoptosis-inducing ligand in vivo. "
  243. (2006). United States Food and Drug Administration approval summary: bortezomib for the treatment of progressive multiple myeloma after one prior therapy. "
  244. (2006). Upregulation of TRAIL-R2 is not involved in HDACi mediated sensitization to TRAIL-induced apoptosis. "
  245. (2002). V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. "
  246. (1998). Z-138: a new mature B-cell acute lymphoblastic leukemia cell line from a patient with transformed chronic lymphocytic leukemia. "
  247. (2003). ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. "

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.