scholarly journals BCL-2 Proteins in Pathogenesis and Therapy of B-Cell Non-Hodgkin Lymphomas

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 938 ◽  
Author(s):  
Magdalena Klanova ◽  
Pavel Klener
Keyword(s):  
B Cell ◽  
Protein Interactions ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Mitochondrial Apoptosis ◽  
Clinical Testing ◽  
Cell Leukemia ◽  
The Status ◽  
B Cell Leukemia

The ability to inhibit mitochondrial apoptosis is a hallmark of B-cell non-Hodgkin lymphomas (B-NHL). Activation of mitochondrial apoptosis is tightly controlled by members of B-cell leukemia/lymphoma-2 (BCL-2) family proteins via protein-protein interactions. Altering the balance between anti-apoptotic and pro-apoptotic BCL-2 proteins leads to apoptosis evasion and extended survival of malignant cells. The pro-survival BCL-2 proteins: B-cell leukemia/lymphoma-2 (BCL-2/BCL2), myeloid cell leukemia-1 (MCL-1/MCL1) and B-cell lymphoma-extra large (BCL-XL/BCL2L1) are frequently (over)expressed in B-NHL, which plays a crucial role in lymphoma pathogenesis, disease progression, and drug resistance. The efforts to develop inhibitors of anti-apoptotic BCL-2 proteins have been underway for several decades and molecules targeting anti-apoptotic BCL-2 proteins are in various stages of clinical testing. Venetoclax is a highly specific BCL-2 inhibitor, which has been approved by the US Food and Drug Agency (FDA) for the treatment of patients with chronic lymphocytic leukemia (CLL) and is in advanced clinical testing in other types of B-NHL. In this review, we summarize the biology of BCL-2 proteins and the mechanisms of how these proteins are deregulated in distinct B-NHL subtypes. We describe the mechanism of action of BH3-mimetics and the status of their clinical development in B-NHL. Finally, we summarize the mechanisms of sensitivity/resistance to venetoclax.

scholarly journals The rise of apoptosis: targeting apoptosis in hematologic malignancies

Blood ◽  
2018 ◽  
Vol 132 (12) ◽  
pp. 1248-1264 ◽  
Author(s):  
Rebecca Valentin ◽  
Stephanie Grabow ◽  
Matthew S. Davids
Keyword(s):  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Cell Leukemia ◽  
Apoptotic Pathway ◽  
Non Hodgkin Lymphoma ◽  
B Cell Leukemia

Abstract Dysregulation of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins of the intrinsic apoptotic pathway is fundamental to the pathophysiology of many hematologic malignancies. The BCL-2 family consists of regulatory proteins that either induce apoptosis (proapoptotic) or inhibit it (prosurvival). BCL-2, myeloid cell leukemia-1, and B-cell lymphoma–extra large are prosurvival proteins that are prime targets for anticancer therapy, and molecules targeting each are in various stages of preclinical and clinical development. The US Food and Drug Administration (FDA)-approved BCL-2 inhibitor venetoclax was first proven to be highly effective in chronic lymphocytic leukemia and some B-cell non-Hodgkin lymphoma subtypes. Subsequently, venetoclax was found to be active clinically against a diverse array of hematologic malignancies including multiple myeloma, acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia, and others. Here, we give a brief introduction to BCL-2 family biology and the mechanism of action of BCL-2 Homology 3 (BH3) mimetics, and provide an overview of the clinical data for therapeutically targeting prosurvival proteins in hematologic malignancies, with a focus on BCL-2 inhibition. To prioritize novel agent combinations and predict responders, we discuss the utility of functional assays such as BH3 profiling. Finally, we provide a perspective on how therapies targeting BCL-2 family proteins may be optimally implemented into future therapeutic regimens for hematologic malignancies.

scholarly journals Frequent p53 gene involvement in splenic B-cell leukemia/lymphomas of possible marginal zone origin

Blood ◽  
1994 ◽  
Vol 84 (1) ◽  
pp. 270-278
Author(s):  
L Baldini ◽  
NS Fracchiolla ◽  
LM Cro ◽  
D Trecca ◽  
L Romitti ◽  
...  
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
High Surface ◽  
Bone Marrow Involvement ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Low Grade ◽  
Cell Leukemia ◽  
Mutation Site ◽  
B Cell Leukemia

A phenotypic and molecular evaluation was made of 15 patients with mature B-cell leukemia/lymphoma showing exclusive spleen and bone marrow involvement. According to French-American-British criteria, these cases could not be classified as classical B-cell chronic lymphocytic leukemia, hairy cell leukemia and its variant forms, splenic lymphoma with villous lymphocytes, or leukemic phase non- Hodgkin's lymphoma (NHL; follicular or intermediate type). The immunophenotype pattern (high surface Ig and CD25 expression, and little or no reactivity with CD5, CD23, and CD11c) and cytomorphologic features of these neoplasms suggested an origin in the marginal zone of the spleen. Molecular analysis did not show any involvement of the dominantly acting oncogenes generally associated with lymphoid malignancies (c-myc, bcl-2, bcl-1, Ras), but mutations of the p53 tumor suppressor gene involving exons 5, 6, and 8 were found in 6 cases (6 of 15, 40%). In 4 cases, the p53 alterations consisted of a point mutation leading to amino acid substitution. In the remaining 2 cases, an insertion or deletion resulting in a frame-shift of the protein was observed. In all but 1 of the cases, the wild-type sequence at the mutation site was barely visible, implying the loss of the normal p53 allele in leukemic cells. All of the cases showed a clinical course compatible with that of low-grade NHL, regardless of the p53 loss/mutation. Overall, our data suggest the existence of a form of splenic B-cell leukemia/lymphoma of possible marginal zone origin in which p53 inactivation may play an important pathogenetic role.

scholarly journals BH3 Mimetics for the Treatment of B-Cell Malignancies—Insights and Lessons from the Clinic

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3353
Author(s):  
Victor S. Lin ◽  
Zhuo-Fan Xu ◽  
David C. S. Huang ◽  
Rachel Thijssen
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Effector Proteins ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Bh3 Mimetics ◽  
Bcl2 Family ◽  
Cancer Cell Survival

The discovery of the link between defective apoptotic regulation and cancer cell survival engendered the idea of targeting aberrant components of the apoptotic machinery for cancer therapy. The intrinsic pathway of apoptosis is tightly controlled by interactions amongst members of three distinct subgroups of the B-cell lymphoma 2 (BCL2) family of proteins. The pro-survival BCL2 proteins prevent apoptosis by keeping the pro-apoptotic effector proteins BCL2-associated X protein (BAX) and BCL2 homologous antagonist/killer (BAK) in check, while the BH3-only proteins initiate apoptosis by either neutralizing the pro-survival BCL2 proteins or directly activating the pro-apoptotic effector proteins. This tripartite regulatory mechanism is commonly perturbed in B-cell malignancies facilitating cell death evasion. Over the past two decades, structure-based drug discovery has resulted in the development of a series of small molecules that mimic the function of BH3-only proteins called the BH3 mimetics. The most clinically advanced of these is venetoclax, which is a highly selective inhibitor of BCL2 that has transformed the treatment landscape for chronic lymphocytic leukemia (CLL). Other BH3 mimetics, which selectively target myeloid cell leukemia 1 (MCL1) and B-cell lymphoma extra large (BCLxL), are currently under investigation for use in diverse malignancies. Here, we review the current role of BH3 mimetics in the treatment of CLL and other B-cell malignancies and address open questions in this rapidly evolving field.

scholarly journals Frequent p53 gene involvement in splenic B-cell leukemia/lymphomas of possible marginal zone origin

Blood ◽  
1994 ◽  
Vol 84 (1) ◽  
pp. 270-278 ◽  
Author(s):  
L Baldini ◽  
NS Fracchiolla ◽  
LM Cro ◽  
D Trecca ◽  
L Romitti ◽  
...  
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
High Surface ◽  
Bone Marrow Involvement ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Low Grade ◽  
Cell Leukemia ◽  
Mutation Site ◽  
B Cell Leukemia

Abstract A phenotypic and molecular evaluation was made of 15 patients with mature B-cell leukemia/lymphoma showing exclusive spleen and bone marrow involvement. According to French-American-British criteria, these cases could not be classified as classical B-cell chronic lymphocytic leukemia, hairy cell leukemia and its variant forms, splenic lymphoma with villous lymphocytes, or leukemic phase non- Hodgkin's lymphoma (NHL; follicular or intermediate type). The immunophenotype pattern (high surface Ig and CD25 expression, and little or no reactivity with CD5, CD23, and CD11c) and cytomorphologic features of these neoplasms suggested an origin in the marginal zone of the spleen. Molecular analysis did not show any involvement of the dominantly acting oncogenes generally associated with lymphoid malignancies (c-myc, bcl-2, bcl-1, Ras), but mutations of the p53 tumor suppressor gene involving exons 5, 6, and 8 were found in 6 cases (6 of 15, 40%). In 4 cases, the p53 alterations consisted of a point mutation leading to amino acid substitution. In the remaining 2 cases, an insertion or deletion resulting in a frame-shift of the protein was observed. In all but 1 of the cases, the wild-type sequence at the mutation site was barely visible, implying the loss of the normal p53 allele in leukemic cells. All of the cases showed a clinical course compatible with that of low-grade NHL, regardless of the p53 loss/mutation. Overall, our data suggest the existence of a form of splenic B-cell leukemia/lymphoma of possible marginal zone origin in which p53 inactivation may play an important pathogenetic role.

Differential expression of apoptosis-associated genes in canine mammary tumors

Biologia ◽  
2015 ◽  
Vol 70 (6) ◽  
Author(s):  
Namita Mitra ◽  
Ramneek Verma ◽  
Dipak Deka ◽  
Hitesh N. Pawar ◽  
Naresh K. Sood ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Myeloid Cell ◽  
B Cell Lymphoma ◽  
Mammary Tumors ◽  
Cell Leukemia ◽  
Pcr Assay ◽  
Canine Mammary Tumors ◽  
Poorly Differentiated ◽  
Maximum Expression

AbstractB-cell lymphoma 2 (Bcl-2) and heat shock protein (HSP) families are implicated in various processes of carcinogenesis, owing to their role in regulation of apoptosis and cell cycle, respectively. mRNA expression of Bcl-2, myeloid cell leukemia 1 (Mcl-1), B-cell lymphoma-extra-large (Bcl-xl), Bcl2-associated X (Bax), HSP70 and HSP90-β genes were studied in 30 clinical canine mammary tumors (CMTs). Histological ‘type’ and ‘grade’ were assigned to CMTs and expression was evaluated by SYBR-Green real-time PCR assay. Overall, the tumors exhibited the maximum expression of Bcl-2 amongst the Bcl-2 family members. Sarcoma and carcinosarcoma showed relatively higher expression of Mcl-1, whereas Bcl-2 was over-expressed in carcinoma. In relation to the cancer grades, Bcl-2/Bax ratio tend to increase as the tumor differentiation progressed from well to poorly differentiated. HSP90-β exhibited significantly high expression in carcinoma, carcinosarcoma and all grades of CMTs were suggestive of their elemental role in tumor progression. In conclusion, this study underpins the conjecture that Bcl-2, Mcl-1 and HSP90-β can be used as potential targets of inhibition in future mammary tumor therapeutics.

scholarly journals Pre-B cell leukemia associated with chromosome translocation 1;19

Blood ◽  
1984 ◽  
Vol 63 (3) ◽  
pp. 721-724 ◽  
Author(s):  
AJ Carroll ◽  
WM Crist ◽  
RT Parmley ◽  
M Roper ◽  
MD Cooper ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Chromosome Translocation ◽  
Lymphocytic Leukemia ◽  
Cell Leukemia ◽  
Early Treatment Failure ◽  
Null Cell ◽  
B Cell Leukemia ◽  
T Cell Phenotypes ◽  
Cell Phenotypes

Abstract Chromosome banding studies on 60 children with acute lymphocytic leukemia (ALL), including “null,” pre-B, B, and T cell phenotypes, were performed. In 4 of 17 patients with pre-B cell ALL, we noted a previously undescribed chromosome translocation, t(1;19)(q23;q13). This translocation was not found in patients with “null” cell, B cell, or T cell ALL. Since each patient with the 1;19 translocation experienced early treatment failure, t(1;19)(q23;q13) may mark a subgroup of patients with pre-B cell ALL who have an especially poor prognosis.

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