Anti-CD33-antibodies labelled with the alpha-emitter Bismuth-213 kill CD33-positive acute myeloid leukaemia cells specifically by activation of caspases and break radio- and chemoresistance by inhibition of the anti-apoptotic proteins X-linked inhibitor of apoptosis protein and B-cell lymphoma-extra large

2013 ◽  
Vol 49 (11) ◽  
pp. 2542-2554 ◽  
Author(s):  
Claudia Friesen ◽  
Mareike Roscher ◽  
Inis Hormann ◽  
Oliver Leib ◽  
Sebastian Marx ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
B Cell ◽  
Myeloid Leukaemia ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Protein ◽  
Alpha Emitter ◽  
Apoptosis Protein ◽  
Acute Myeloid

scholarly journals Venetoclax for the treatment of newly diagnosed acute myeloid leukemia in patients who are ineligible for intensive chemotherapy

2019 ◽  
Vol 10 ◽  
pp. 204062071988282 ◽  
Author(s):  
Guillaume Richard-Carpentier ◽  
Courtney D. DiNardo
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Adverse Events ◽  
B Cell ◽  
Drug Administration ◽  
Myeloid Leukemia ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Intensive Chemotherapy ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a globally poor outcome, especially in patients ineligible for intensive chemotherapy. Until recently, therapeutic options for these patients included low-dose cytarabine (LDAC) or the hypomethylating agents (HMA) azacitidine and decitabine, which have historically provided only short-lived and modest benefits. The oral B-cell lymphoma 2 inhibitor, venetoclax, Venetoclax, an oral B-cell lymphoma 2 (BCL2) inhibitor, is now approved by the USA Food and Drug Administration (FDA) in combination with LDAC or HMA in older AML patients ineligible for intensive chemotherapy. Is now approved by the US Food and Drug Administration for this indication. In the pivotal clinical trials evaluating venetoclax either in combination with LDAC or with HMA, the rates of complete remission (CR) plus CR with incomplete hematological recovery were 54% and 67%, respectively and the median overall survival (OS) was 10.4 months and 17.5 months, respectively, comparing favorably with outcomes in clinical trials evaluating single-agent LDAC or HMA. The most common adverse events with venetoclax combinations are gastrointestinal symptoms, which are primarily low grade and easily manageable, and myelosuppression, which may require delays between cycles, granulocyte colony-stimulating factor (G-CSF) administration, or decreased duration of venetoclax administration per cycle. A bone marrow assessment after the first cycle of treatment is critical to determine dosing and timing of subsequent cycles, as most patients will achieve their best response after one cycle. Appropriate prophylactic measures can reduce the risk of venetoclax-induced tumor lysis syndrome. In this review, we present clinical data from the pivotal trials evaluating venetoclax-based combinations in older patients ineligible for intensive chemotherapy, and provide practical recommendations for the prevention and management of adverse events associated with venetoclax.

scholarly journals Targeting Apoptotic Pathways in Acute Myeloid Leukaemia

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1660 ◽  
Author(s):  
Jonathan R. Sillar ◽  
Anoop K. Enjeti
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
B Cell Lymphoma ◽  
Clinical Work ◽  
Biological Research ◽  
Apoptotic Pathways ◽  
Molecular Landscape ◽  
Early Phase Clinical Trials ◽  
Acute Myeloid

Acute Myeloid Leukaemia is a devastating disease that continues to have a poor outcome for the majority of patients. In recent years, however, a number of drugs have received FDA approval, following on from successful clinical trial results. This parallels the characterization of the molecular landscape of Acute Myeloid Leukaemia (AML) over the last decade, which has led to the development of drugs targeting newly identified recurring mutations. In addition, basic biological research into the pathobiology of AML has identified aberrant programmed cell death pathways in AML. Following on from successful outcomes in lymphoid malignancies, drugs targeting the B Cell Lymphoma 2 (BCL-2) family of anti-apoptotic proteins have been explored in AML. In this review, we will outline the preclinical and clinical work to date supporting the role of drugs targeting BCL-2, with Venetoclax being the most advanced to date. We will also highlight rationale combinations using Venetoclax, ongoing clinical trials and biomarkers of response identified from the early phase clinical trials performed.

Expression of X-Linked Inhibitor of Apoptosis Protein in Reactive Lymphoid Tissues, Non-Hodgkin’s Lymphomas, and Hodgkin’s Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4655-4655
Author(s):  
James A. Strauchen ◽  
David Burstein
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
Hodgkin Disease ◽  
Large B Cell Lymphoma ◽  
Apoptosis Protein ◽  
Mantle Cell ◽  
Large B Cell

Abstract X-linked inhibitor of apoptosis protein (XIAP) is an important regulator of apoptosis which binds to and inhibits caspases-3, -7 and -9, blocking the caspase 9-mediated apoptosis pathway. This pathway is activated by p53 and DNA damage and may be an important determinant of responsiveness to chemotherapy. Apoptosis also plays a major role in the regulation of follicle center B-cell proliferation and BCL2-mediated inhibition of apoptosis is a key factor in B-cell lymphomagenesis. In this study we examined the expression of XIAP in 65 reactive and neoplastic lymphoid proliferations utilizing a monoclonal antibody to XIAP (#610763 BD Biosciences, San Jose, CA) and immunohistochemistry with avidin-biotin-complex immunoperoxidase technique on formalin-fixed, paraffin-embedded sections. In reactive lymph nodes and tonsils, expression of XIAP was limited to large noncleaved cells in follicle centers (5 of 6 cases). XIAP was absent in plasmacytoma (3 cases) and small lymphocytic lymphoma/chronic lymphocytic leukemia (1 case). XIAP was expressed in follicular lymphoma, predominantly in large noncleaved cells (6 of 9 cases) and in diffuse large B cell lymphoma (11 of 16 cases), including cases of T-cell/histiocyte-rich diffuse large B cell lymphoma (2 cases), primary mediastinal large B cell lymphoma (1 case), and posttransplantation diffuse large B cell lymphoma (1 case). XIAP was consistently expressed in Burkitt and Burkitt-like lymphoma (3 of 3 cases) and anaplastic large cell lymphoma (3 of 3 cases) and in one case of adult T cell leukemia/lymphoma. XIAP was variably expressed in marginal-zone B cell lymphoma, predominantly in large blasts (2 of 4 cases) and in mantle cell lymphoma (2 of 3 cases). XIAP was not detected in peripheral T cell lymphoma, unspecified (1 case), extranodal NK/T cell lymphoma, nasal type (1 case), precursor B cell lymphoblastic leukemia (1 case), or granulocytic sarcoma (1 case). XIAP was consistently expressed in the Reed-Sternberg and mononuclear Reed-Sternberg-variant cells of classical Hodgkin disease (9 of 9 cases) and the L+H Reed-Sternberg-variant cells of nodular lymphocyte predominance Hodgkin disease (3 of 3 cases). XIAP is expressed across a broad range of lymphoproliferative disorders, including classical and nodular lymphocyte predominance Hodgkin disease, diffuse large B cell lymphoma, follicular lymphoma, Burkitt lymphoma, marginal-zone and mantle cell lymphoma, and anaplastic large cell lymphoma. XIAP appears to be selectively expressed in the proliferating elements of these lymphomas. The possible prognostic and therapeutic significance of XIAP expression needs to be determined.

Translocation of the inhibitor of apoptosis protein c-IAP1 from the nucleus to the Golgi in hematopoietic cells undergoing differentiation: a nuclear export signal-mediated event

Blood ◽  
2004 ◽  
Vol 104 (7) ◽  
pp. 2035-2043 ◽  
Author(s):  
Stéphanie Plenchette ◽  
Séverine Cathelin ◽  
Cédric Rébé ◽  
Sophie Launay ◽  
Sylvain Ladoire ◽  
...  
Keyword(s):  
Cell Lines ◽  
Nuclear Export ◽  
Nuclear Export Signal ◽  
B Cell Lymphoma ◽  
Site Directed Mutagenesis ◽  
Inhibitor Of Apoptosis ◽  
Monocytic Cell ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein ◽  
Export Signal

Abstract The caspase inhibitor and RING finger-containing protein cellular inhibitor of apoptosis protein 1 (c-IAP1) has been shown to be involved in both apoptosis inhibition and signaling by members of the tumor necrosis factor (TNF) receptor family. The protein is regulated transcriptionally (eg, is a target for nuclear factor-κB [NF-κB]) and can be inhibited by mitochondrial proteins released in the cytoplasm upon apoptotic stimuli. The present study indicates that an additional level of regulation of c-IAP1 may be cell compartmentalization. The protein is present in the nucleus of undifferentiated U937 and THP1 monocytic cell lines. When these cells undergo differentiation under phorbol ester exposure, c-IAP1 translocates to the cytoplasmic side of the Golgi apparatus. This redistribution involves a nuclear export signal (NES)-mediated, leptomycin B-sensitive mechanism. Using site-directed mutagenesis, we localized the functional NES motif in the caspase recruitment domain (CARD) of c-IAP1. A nucleocytoplasmic redistribution of the protein was also observed in human monocytes as well as in tumor cells from epithelial origin when undergoing differentiation. c-IAP1 does not translocate from the nucleus of cells whose differentiation is blocked (ie, in cell lines and monocytes from transgenic mice overexpressing B-cell lymphoma 2 [Bcl-2] and in monocytes from patients with chronic myelomonocytic leukemia). Altogether, these observations associate c-IAP1 cellular location with cell differentiation, which opens new perspectives on the functions of the protein. (Blood. 2004;104:2035-2043)

scholarly journals Synchronous Occurrence of Mycosis Fungoides, Diffuse Large B Cell Lymphoma and Acute Myeloid Leukemia

2018 ◽  
Vol 57 (10) ◽  
pp. 1445-1453 ◽  
Author(s):  
Junichi Miyatake ◽  
Hiroaki Inoue ◽  
Kentarou Serizawa ◽  
Yasuyoshi Morita ◽  
JL Espinoza ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
B Cell ◽  
Mycosis Fungoides ◽  
Myeloid Leukemia ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Acute Myeloid

scholarly journals Quadri-lineage disease involving nodal B-cell marginal zone lymphoma, high-grade B-cell lymphoma, Kaposi's syndrome, and acute myeloid leukemia

2015 ◽  
Vol 4 (1) ◽  
pp. 39-42 ◽  
Author(s):  
Kamel Laribi ◽  
Habib Ghnaya ◽  
Pierre-Jean Mention ◽  
Hoel Rousset ◽  
Alix Baugier de Materre ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
B Cell ◽  
Myeloid Leukemia ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
High Grade ◽  
Acute Myeloid
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