BCL2 (B-Cell Leukemia/Lymphoma 2)

2017-12-01   Anwar N Mohamed 

Cytogenetics Laboratory, Pathology Department, Detroit Medical Center, Wayne State University School of Medicine, Detroit, MI USA; amohamed@dmc.org

Identity

HGNC
LOCATION
18q21.33
IMAGE
Atlas Image
LEGEND
Figure 1 BCL2 (18q21) PAC 248E24 - Courtesy Mariano Rocchi
LOCUSID
ALIAS
Bcl-2,PPP1R50
FUSION GENES

Abstract

BCL2 is the milestone of apoptosis-regulatory genes. It contributes to tumorigenesis by blocking programmed cell death as such, promoting cell survival. The aberrant expression of BCL2 gene is strongly associated with resistance to chemotherapy and radiation. This review outlines the structure, function, and role of BCL2 gene in cancer.

DNA/RNA

Description

The human BCL2 gene has a three exon structure with an untranslated first exon, a facultative 220 bp intron I, and a large 370 kb intron II. The native BCL2 gene has a long 3 untranslated regions and two distinct promoters, P1 and P2. The main promoter region, P1, is a TATA-less, GC-rich promoter containing multiple transcriptional start sites and located 1386-1423 bp upstream of the translation start site. The use of alternative promoter results in mRNAs comprised of exons II/III or I/II/III. The t(14;18) translocation in B-cells generates heterogeneous 4.2 - 7.2 kb BCL2-IGH chimeric mRNAs resulting from alternative BCL2 5 exons and varied IGH 3 untranslated regions. The t(14;18) does not interrupt the BCL2 open reading frame, however, inappropriately high levels of BCL2-IGH mRNAs are present. The native BCL2 and BCL2-IGH fusion mRNAs demonstrate the same 2.5-hour short half-life (Clearly et al, 1986, Tsujimoto et al1986, Seta et al1988)

Proteins

Atlas Image

Description

The BCL2 gene encodes a 26 kd protein consisting of 239 amino acids with a single highly hydrophobic domain at its C-terminus, which enables it to localize mainly in the mitochondrial outer membrane, and to a lesser extent in the nuclear envelope and the membrane of the endoplasmic reticulum (Chen-Levy 1989). The main role of BCL2 protein is to maintain the integrity of the mitochondrial membrane, preventing cytochrome c release and its subsequent binding to APAF1 (apoptosis activating factor-1). The protein contains all four BCL2 homology (BH) domains (BH1 to BH4). BH1, BH2 and BH3 constitute the hydrophobic cleft through which the protein interacts and forms homo- and heterodimers with the pro-apoptotic members of the BCL2 family of proteins (Thomadaki 2006, Reed 2006). BCL2 increases the survival kinetics of the cell specifically by blocking apoptosis. Thus it prevents the cell from going into suicidal activities that usually require ATP, new RNA, and protein synthesis, and inducing a variety of cellular ultra-structural changes such as cell shrinkage, nuclear fragmentation, and DNA degradation.

Expression

BCL2 expression is widespread in immature tissues prenatally whereas its expression becomes highly restricted with maturation. BCL2 is extensively expressed in immature B-cells and memory B cells but is temporarily down-regulated in germinal center B-cells, partially because of repression by BCL6. High levels of BCL2 have been detected in thymus throughout the medulla, in spleen and in lymph nodes as well as early in the embryonic kidney. Decrease in its expression levels is observed in motor-neurons as well as in pre-B cells being prepared to differentiate (Thomadaki 2006).

Function

BCL2 Protein Family and Apoptosis
The BCL2 family is a prototype of a large family of evolutionarily related proteins that share a high degree of homology although they exert different functions. This family consists of 25 pro-apoptotic and anti-apoptotic members which interact to maintain a balance between newly forming cells and old dying cells. These proteins are localized to the membrane of mitochondria and endoplasmic reticulum, operating as guardians of these organelles (Thomadaki 2006, Reed 2008, Aki etal 2014)). BCL2 family proteins play central roles in cell death regulation and can regulate diverse cell death mechanisms including apoptosis, necrosis and autophagy. They are the key regulators of the mitochondrial pathway of apoptosis. This pathway is required for normal embryonic development and for preventing cancer. These proteins control the permeabilization of the mitochondrial outer membrane (MOM) that releases cytochrome c and other apoptotic factors into the cytosol. BCL2 family proteins share up to four BCL2 homology domains (BH1, BH2, BH3, & BH4) and are generally divided into two categories, anti-apoptotic and pro-apoptotic proteins based on their intracellular function and sequence homology. The anti-apoptotic proteins, BCL2, BCL2L1 (BCL-XL), BCL2L2 (BCL-W), MCL1, BCL2A1 (A1/BFL-1), share homology within four domains (BH1-4). These proteins form a characteristic helical bundle fold, which is critical for their ability to bind to the pro-apoptotic BCL2 family members and thereby exert their antiapoptotic function. The pro-apoptotic proteins such as BAX, BAK1, and BOK share BH1-3 domains whereas other pro-apoptotic proteins, such as BCL2L11 (BIM), BAD, and BID, contain only the BH3 domain and are known as BH3-only proteins (Figure 3). In normal situations, the BH3-only proteins are inactive or exist at low levels in the cell. However, in the presence of apoptotic stimuli the BH-only proteins become activated by post-translational modifications or their expression are increased. The stimulation of BH3-only proteins induces BAX-BAK oligomerization. After their oligomerization, BAX and BAK directly cause MOM permeabilization, a critical step in apoptosis (Aki et al 2014). The role of anti-apoptotic BCL2 proteins is to neutralize pro-apoptotic BH3-only proteins and thus inhibit their effect on BAX-BAK activity and MOM permeabilization. The balance between pro-survival and pro-death BCL-2 proteins is a major factor in determining if cells undergo apoptosis in response to cell stress.
Control of Proliferation by BCL2
Although BCL2-family proteins are key players in the control of mitochondria-based apoptosis, they can also control cell proliferation. High levels of BCL2 protein were reported to be associated with a lower proliferative capacity of human lymphoma, suggesting a negative control on proliferation. The anti-proliferative effect of BCL2 acts mainly at the level of the G0/G1 phase of the cell cycle. Deletions and point mutations in the BCL2 gene show that in some cases the anti-proliferative activity of BCL2 can be dissociated from its anti-apoptotic function (Bonnefoy et al, 2004). This indicates that the effect of BCL2 on cell cycle progression can be a direct effect and not only a consequence of its anti-apoptotic activity. BCL2 appears to mediate its anti-proliferative effect by acting on both signal transduction pathways ( NFAT, ERK) and on specific cell cycle regulators. In addition, BCL2 cooperated with MYC to promote proliferation of B-cell precursors.
Atlas Image
Figure 3 BCL-family proteins have 1-4 domains (BH1, BH2, BH3 or BH4) and a transmembrane domain (TM). Anti-apoptotic BCL2-family members contain all four BH domains. Proapoptotic BCL2-family members are either multi-domain or BH3-only proteins.

Implicated in

Top note
Apoptosis is essential for normal embryonic development, maintenance of tissue homeostasis, and development and function of the immune system. In contrast, processes that interfere with normal apoptosis promote cell survival and, potentially, oncogenesis. Therefore, dysregulation of BCL2 family has a major role in tumor formation. The BCL2 family is also involved in other diseases, such as autoimmune, infectious and neurodegenerative disorders. The autoimmune disease such as type I diabetes can be caused by defective apoptosis, and schizophrenia may result from an abnormal ratio of pro- and anti-apoptotic factors (Strasser et al, 2011). On the other hand, there is increasing evidence that BCL2 family proteins also have additional functions in other cellular processes, such as mitochondrial morphology and metabolism, which remain largely unexplored. Apoptosis is regulated by a balance of pro-apoptotic factors and anti-apoptotic factors.
Entity name
t(14;18)(q32;q21)
Disease
The t(14;18) Breakpoints in Lymphoma
The t(14;18)(q32;q21) constitutes the most common chromosomal translocation in human lymphomas, being present in over 85% of follicular lymphoma (FL) and in up to 30% of diffuse large B-cell lymphoma (DLBCL). BCL2 is normally located on chromosome 18q21.33 in a telomere to centromere orientation. The molecular consequence of the t(14;18) juxtaposes of the BCL2 gene next to IGH locus on the der(14) chromosome, in the same transcriptional orientation as the IGH gene. The breakpoints on chromosome 18 are clustered with 50-60% fall within a 2.8 kb major breakpoint region (MBR), located in the untranslated 3? UTR of the BCL2 gene, and another 25% falls in the minor cluster region (MCR) (Bakhshi 1987, Willis and Dyer 2000). Others cluster within a third, intermediate cluster region midway between the MBR and MCR while other breakpoints have been described scattered through this region. In rare variant translocations involving the IG light chain loci, t(2;18)(p12;q21) and t(18;22)(q21;q11.2), the breakpoints are located in the 5? noncoding region of the BCL2 gene. The breakpoints on chromosome 14 occur most commonly just 5? of IGH JH segments within sequences that typically show evidence of exonucleolytic "nibbling", N-bp additions, and D segment addition, events that occur normally during attempted V(D)J recombination. Less commonly, IGH breakpoints may occur at sites 3? of the JH segments, or rarely even in IG switch regions. BCL2 mRNA expression is up-regulated in the translocated allele through the action of IGH E[] enhancer sequences, which are highly active in germinal center B cells. In the cases of rearrangements falling in the MBR, a BCL2/IGH fusion mRNA transcript is produced whereas rearrangements in the MCR lead to increased levels of a normal BCL2 mRNA (Aster and longtine 2002). The t(14;18) translocation or its variants does not interrupt the protein-encoding region of BCL2 gene so that the normal and the translocated alleles produce the same-sized, 26-kd protein, a member of a family of proteins involved in the regulation of apoptosis. The somatic hypermutation mechanism associated with the IGH gene often induces mutations in the BCL2 gene which may further dysregulate its expression and can also lead to point mutations in the coding regions of the BCL2 protein (Seto 1988, Tanaka et al 1992). Therefore, a subset of t(14;18) positive lymphomas do not express intact BCL2 protein due to somatic mutations of the gene.
The majority of follicular lymphomas in adults depend on BCL2 overexpression which is almost always the result of t(14;18) translocation or its variants. BCL2 overexpression sustains cell survival but is not sufficient for FL development, thus other genetic lesions or epigenetic events are required. This is supported by the observation that BCL2 transgenic mice develop polyclonal hyperplasia of mature, long lived non-dividing B cells. With time, a fraction of BCL2 transgenic mice develops aggressive, clonal large cell lymphomas, which have acquired additional genetic lesions (McDonnell et al 1988).
Cytogenetics
Diagnostic use of BCL2
Fluorescence in situ hybridization (FISH) is widely used in clinical laboratories to detect BCL2 gene rearrangement in fresh tissue and paraffin embedded tissue sections using dual color translocation DNA probes (Figure 4). BCL2 protein expression by immuno-histochemistry represents a rapid and inexpensive method to identify BCL2 overexpression. In normal tissue, BCL2 antibodies react with B-cells in the mantle zone, as well as some T-cells. Because BCL2 expression is down-regulated in normal germinal centers, the presence of BCL2 protein can help to distinguish follicular lymphomas from reactive follicular hyperplasia. However, positive cells increase considerably in follicular lymphoma, as well as many other forms of cancer. In some cases, the presence or absence of BCL2 staining in biopsies may be significant for the patients prognosis or likelihood of relapse.
Atlas Image
Figure 4 Karyotype from follicular lymphoma showing t(14;18)(q32;q21) [arrow]; Insert: FISH with IGH/BCL2 DNA probes showing a double fusion signals confirming t(14;18) [red &green fused signals]
Note

Bibliography

Pubmed IDLast YearTitleAuthors
247687142014A dual role for the anti-apoptotic Bcl-2 protein in cancer: mitochondria versus endoplasmic reticulum.Akl H et al
204596952010High expression of BCL-2 predicts favorable outcome in non-small cell lung cancer patients with non squamous histology.Anagnostou VK et al
118911732002Detection of BCL2 rearrangements in follicular lymphoma.Aster JC et al
39244121985Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18.Bakhshi A et al
31049141987Mechanism of the t(14;18) chromosomal translocation: structural analysis of both derivative 14 and 18 reciprocal partners.Bakhshi A et al
149965002004Control of proliferation by Bcl-2 family members.Bonnefoy-Berard N et al
76846241993High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy.Campos L et al
26519031989The bcl-2 candidate proto-oncogene product is a 24-kilodalton integral-membrane protein highly expressed in lymphoid cell lines and lymphomas carrying the t(14;18) translocation.Chen-Levy Z et al
161662622005miR-15 and miR-16 induce apoptosis by targeting BCL2.Cimmino A et al
28757991986Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation.Cleary ML et al
268225772016Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies.Delbridge AR et al
270432332016Hematologic malignancies: newer strategies to counter the BCL-2 protein.Ebrahim AS et al
81045321993bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia.Hanada M et al
76402181995Prognostic value of bcl-2 expression in invasive breast cancer.Hellemans P et al
83974061993Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death.Henderson S et al
75774911995Expression and prognostic significance of Bcl-2 in ovarian tumours.Henriksen R et al
152179672004Oblimersen sodium (Genasense bcl-2 antisense oligonucleotide): a rational therapeutic to enhance apoptosis in therapy of lung cancer.Herbst RS et al
164184942006BCL2 expression is a prognostic marker for the activated B-cell-like type of diffuse large B-cell lymphoma.Iqbal J et al
74906791995Expression of bcl-2 oncogene protein is prevalent in small cell lung carcinomas.Jiang SX et al
196415032008BH3-only proteins in apoptosis and beyond: an overview.Lomonosova E et al
26492471989bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation.McDonnell TJ et al
92425491997BCL2 overexpression associated with chromosomal amplification in diffuse large B-cell lymphoma.Monni O et al
183622122008Bcl-2-family proteins and hematologic malignancies: history and future prospects.Reed JC et al
28341971988Alternative promoters and exons, somatic mutation and deregulation of the Bcl-2-Ig fusion gene in lymphoma.Seto M et al
218630202011Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases.Strasser A et al
13392991992Frequent incidence of somatic mutations in translocated BCL2 oncogenes of non-Hodgkin's lymphomas.Tanaka S et al
165312742006BCL2 family of apoptosis-related genes: functions and clinical implications in cancer.Thomadaki H et al
35234871986Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma.Tsujimoto Y et al
32622021988Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells.Vaux DL et al
109108912000The role of immunoglobulin translocations in the pathogenesis of B-cell malignancies.Willis TG et al
189559682008Bcl-2 family proteins and cancer.Yip KW et al

Other Information

Locus ID:

NCBI: 596
MIM: 151430
HGNC: 990
Ensembl: ENSG00000171791

Variants:

dbSNP: 596
ClinVar: 596
TCGA: ENSG00000171791
COSMIC: BCL2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000171791ENST00000333681P10415
ENSG00000171791ENST00000333681A0A024R2B3
ENSG00000171791ENST00000398117P10415
ENSG00000171791ENST00000398117A0A024R2B3
ENSG00000171791ENST00000589955P10415
ENSG00000171791ENST00000589955A0A024R2C4

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45
50

Pathways

PathwaySourceExternal ID
Autophagy - animalKEGGko04140
ApoptosisKEGGko04210
Hedgehog signaling pathwayKEGGko04340
Focal adhesionKEGGko04510
Jak-STAT signaling pathwayKEGGko04630
Amyotrophic lateral sclerosis (ALS)KEGGko05014
Colorectal cancerKEGGko05210
Prostate cancerKEGGko05215
Small cell lung cancerKEGGko05222
Autophagy - animalKEGGhsa04140
ApoptosisKEGGhsa04210
Hedgehog signaling pathwayKEGGhsa04340
Focal adhesionKEGGhsa04510
Jak-STAT signaling pathwayKEGGhsa04630
Amyotrophic lateral sclerosis (ALS)KEGGhsa05014
Pathways in cancerKEGGhsa05200
Colorectal cancerKEGGhsa05210
Prostate cancerKEGGhsa05215
Small cell lung cancerKEGGhsa05222
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
Protein processing in endoplasmic reticulumKEGGko04141
Protein processing in endoplasmic reticulumKEGGhsa04141
ToxoplasmosisKEGGko05145
ToxoplasmosisKEGGhsa05145
TuberculosisKEGGko05152
TuberculosisKEGGhsa05152
Cholinergic synapseKEGGhsa04725
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
NF-kappa B signaling pathwayKEGGhsa04064
NF-kappa B signaling pathwayKEGGko04064
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Hepatitis BKEGGhsa05161
HIF-1 signaling pathwayKEGGhsa04066
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Adrenergic signaling in cardiomyocytesKEGGhsa04261
Adrenergic signaling in cardiomyocytesKEGGko04261
Sphingolipid signaling pathwayKEGGhsa04071
Sphingolipid signaling pathwayKEGGko04071
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathwaysREACTOMER-HSA-168643
InflammasomesREACTOMER-HSA-622312
The NLRP1 inflammasomeREACTOMER-HSA-844455
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Programmed Cell DeathREACTOMER-HSA-5357801
ApoptosisREACTOMER-HSA-109581
Intrinsic Pathway for ApoptosisREACTOMER-HSA-109606
Activation of BH3-only proteinsREACTOMER-HSA-114452
Activation of BAD and translocation to mitochondriaREACTOMER-HSA-111447
BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 membersREACTOMER-HSA-111453
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933
Apoptosis - multiple speciesKEGGko04215
Apoptosis - multiple speciesKEGGhsa04215
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
Platinum drug resistanceKEGGko01524
Endocrine resistanceKEGGko01522
Platinum drug resistanceKEGGhsa01524
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
Endocrine resistanceKEGGhsa01522
Interleukin-4 and 13 signalingREACTOMER-HSA-6785807
Fluid shear stress and atherosclerosisKEGGko05418
Fluid shear stress and atherosclerosisKEGGhsa05418

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA444445Hepatitis CDiseaseClinicalAnnotationassociatedPD21159314
PA445204Ovarian NeoplasmsDiseaseClinicalAnnotationassociatedPD23963862
PA448803carboplatinChemicalClinicalAnnotationassociatedPD23963862
PA449383docetaxelChemicalClinicalAnnotationassociatedPD23963862
PA450761paclitaxelChemicalClinicalAnnotationassociatedPD23963862
PA451241ribavirinChemicalClinicalAnnotationassociatedPD21159314
PA451879vincristineChemicalPathwayassociated
PA451999interferonsChemicalClinicalAnnotationassociatedPD21159314

References

Pubmed IDYearTitleCitations
161662622005miR-15 and miR-16 induce apoptosis by targeting BCL2.1144
122091542002The Bcl2 family: regulators of the cellular life-or-death switch.901
185708712008JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy.487
159016722005Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins.472
266393482016Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.363
183143332008How do BCL-2 proteins induce mitochondrial outer membrane permeabilization?356
172007142007Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737.223
149802202004Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3.210
228515652012Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.205
120866702002Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability.193

Citation

Anwar N Mohamed

BCL2 (B-Cell Leukemia/Lymphoma 2)

Atlas Genet Cytogenet Oncol Haematol. 2017-12-01

Online version: http://atlasgeneticsoncology.org/gene/49/bcl2

Historical Card

1998-05-01 BCL2 (B-Cell Leukemia/Lymphoma 2) by  Jean-Loup Huret 

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France