BCL2A1: the underdog in the BCL2 family

B-cell lymphoma 2 (BCL2) proteins are important cell death regulators, whose main function is to control the release of cytochrome c from mitochondria in the intrinsic apoptotic pathway. They comprise both pro- and anti-apoptotic proteins, which interact in various ways to induce or prevent pore formation in the outer mitochondrial membrane. Due to their central function in the apoptotic machinery, BCL2 proteins are often deregulated in cancer. To this end, many anti-apoptotic BCL2 proteins have been identified as important cellular oncogenes and attractive targets for anti-cancer therapy. In this review, the existing knowledge on B-cell lymphoma 2-related protein A1 (BCL2A1)/Bcl-2-related gene expressed in fetal liver (Bfl-1), one of the less extensively studied anti-apoptotic BCL2 proteins, is summarized. BCL2A1 is a highly regulated nuclear factor κB (NF-κB) target gene that exerts important pro-survival functions. In a physiological context, BCL2A1 is mainly expressed in the hematopoietic system, where it facilitates survival of selected leukocytes subsets and inflammation. However, BCL2A1 is overexpressed in a variety of cancer cells, including hematological malignancies and solid tumors, and may contribute to tumor progression. Therefore, the development of small molecule inhibitors of BCL2A1 may be a promising approach mainly to sensitize tumor cells for apoptosis and thus improve the efficiency of anti-cancer therapy.

[1]  John Calvin Reed,et al.  Differential Regulation of Bax and Bak by Anti-apoptotic Bcl-2 Family Proteins Bcl-B and Mcl-1* , 2008, Journal of Biological Chemistry.

[2]  A. Villunger,et al.  BH3-only proteins in cell death initiation, malignant disease and anticancer therapy , 2006, Cell Death and Differentiation.

[3]  A. Strasser,et al.  The BCL-2 protein family: opposing activities that mediate cell death , 2008, Nature Reviews Molecular Cell Biology.

[4]  Catherine Charbonnel,et al.  Prediction of metastatic relapse in node-positive breast cancer: establishment of a clinicogenomic model after FEC100 adjuvant regimen , 2008, Breast Cancer Research and Treatment.

[5]  M. Trescol-Biémont,et al.  Downregulation of Bfl-1 protein expression sensitizes malignant B cells to apoptosis , 2007, Oncogene.

[6]  S. Tait,et al.  Bcl-2 Family Member Bfl-1/A1 Sequesters Truncated Bid to Inhibit Its Collaboration with Pro-apoptotic Bak or Bax* , 2002, The Journal of Biological Chemistry.

[7]  Y. Shim,et al.  Bfl-1S, a novel alternative splice variant of Bfl-1, localizes in the nucleus via its C-terminus and prevents cell death , 2003, Oncogene.

[8]  Malay Mandal,et al.  The BCL2A1 gene as a pre–T cell receptor–induced regulator of thymocyte survival , 2005, The Journal of experimental medicine.

[9]  G M Cohen,et al.  Different forms of cell death induced by putative BCL2 inhibitors , 2009, Cell Death and Differentiation.

[10]  C Gélinas,et al.  The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNFalpha-induced apoptosis. , 1999, Genes & development.

[11]  D. Loh,et al.  Multiple gene duplication and expression of mouse bcl-2-related genes, A1. , 1998, International immunology.

[12]  J. Tschopp,et al.  Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors , 1997, Nature.

[13]  Derek W. Yecies,et al.  Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. , 2010, Blood.

[14]  W. Zong,et al.  Bfl-1/A1 functions, similar to Mcl-1, as a selective tBid and Bak antagonist , 2008, Oncogene.

[15]  R. Wickremasinghe,et al.  Monocytes stimulate expression of the Bcl-2 family member, A1, in endothelial cells and confer protection against apoptosis. , 1999, Journal of immunology.

[16]  E. Remmerswaal,et al.  CD40 stimulation of B‐cell chronic lymphocytic leukaemia cells enhances the anti‐apoptotic profile, but also Bid expression and cells remain susceptible to autologous cytotoxic T‐lymphocyte attack , 2004, British journal of haematology.

[17]  M. Lanotte,et al.  Gene expression networks underlying retinoic acid-induced differentiation of acute promyelocytic leukemia cells. , 2000, Blood.

[18]  M. Hinds,et al.  Structural plasticity underpins promiscuous binding of the prosurvival protein A1. , 2008, Structure.

[19]  S. Cory,et al.  The Bcl-2 apoptotic switch in cancer development and therapy , 2007, Oncogene.

[20]  B. Torbett,et al.  The anti-apoptotic gene BCL2A1 is a novel transcriptional target of PU.1 , 2010, Leukemia.

[21]  A. Karsan,et al.  Cloning of human Bcl-2 homologue: inflammatory cytokines induce human A1 in cultured endothelial cells. , 1996, Blood.

[22]  I. Berberich,et al.  The Stability and Anti-apoptotic Function of A1 Are Controlled by Its C Terminus* , 2006, Journal of Biological Chemistry.

[23]  Allen R. Chen,et al.  The antiapoptotic gene A1/BFL1 is a WT1 target gene that mediates granulocytic differentiation and resistance to chemotherapy. , 2006, Blood.

[24]  Z. Oltvai,et al.  Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[25]  S. Cory,et al.  Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members , 1999, Cell Death and Differentiation.

[26]  M. Berger,et al.  Characterization of A1, a novel hemopoietic-specific early-response gene with sequence similarity to bcl-2. , 1993, Journal of immunology.

[27]  R. Rosenquist,et al.  Upregulation of bfl-1 is a potential mechanism of chemoresistance in B-cell chronic lymphocytic leukaemia , 2007, British Journal of Cancer.

[28]  C. Tse,et al.  ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. , 2008, Cancer research.

[29]  T. McDonnell,et al.  Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18) , 1991, Nature.

[30]  J. Marvel,et al.  A1/Bfl-1 expression is restricted to TCR engagement in T lymphocytes , 2003, Cell Death and Differentiation.

[31]  A. Ferrer,et al.  Abnormal expression of apoptosis‐related genes in haematological malignancies: overexpression of MYC is poor prognostic sign in mantle cell lymphoma , 2003, British journal of haematology.

[32]  G. Chinnadurai,et al.  bfl-1, a bcl-2 homologue, suppresses p53-induced apoptosis and exhibits potent cooperative transforming activity. , 1996, Cancer research.

[33]  W. Greenhalf,et al.  Structural Basis of BFL-1 for Its Interaction with BAX and Its Anti-apoptotic Action in Mammalian and Yeast Cells* , 2000, The Journal of Biological Chemistry.

[34]  F. Martinon,et al.  The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. , 2002, Molecular cell.

[35]  Y. Ron,et al.  Defective ubiquitin-mediated degradation of antiapoptotic Bfl-1 predisposes to lymphoma. , 2010, Blood.

[36]  V. Pantesco,et al.  Gene expression of anti‐ and pro‐apoptotic proteins in malignant and normal plasma cells , 2009, British journal of haematology.

[37]  Q Cheng,et al.  NF-kappaB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[38]  M. Bickle,et al.  Characterization of peptide aptamers targeting Bfl-1 anti-apoptotic protein. , 2011, Biochemistry.

[39]  C. Kurschner,et al.  Modulation of Cell Death in Yeast by the Bcl-2 Family of Proteins* , 1997, The Journal of Biological Chemistry.

[40]  D. Rawlings,et al.  Transitional B Lymphocyte Subsets Operate as Distinct Checkpoints in Murine Splenic B Cell Development1 , 2002, The Journal of Immunology.

[41]  M. Berger,et al.  Novel expression pattern of a new member of the MIP-1 family of cytokine-like genes. , 1991, Cell regulation.

[42]  Pär Nordlund,et al.  Completing the family portrait of the anti‐apoptotic Bcl‐2 proteins: Crystal structure of human Bfl‐1 in complex with Bim , 2008, FEBS letters.

[43]  Marty W. Mayo,et al.  NF-κB Induces Expression of the Bcl-2 Homologue A1/Bfl-1 To Preferentially Suppress Chemotherapy-Induced Apoptosis , 1999, Molecular and Cellular Biology.

[44]  Z. Ling,et al.  Genomic-wide analysis of lymphatic metastasis-associated genes in human hepatocellular carcinoma. , 2009, World journal of gastroenterology.

[45]  S. Gerondakis,et al.  Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. , 1999, Genes & development.

[46]  A. Morales,et al.  High expression of Bfl‐1 contributes to the apoptosis resistant phenotype in B‐cell chronic lymphocytic leukemia , 2005, International journal of cancer.

[47]  Reuven Rasooly,et al.  Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Naive T Lymphocytes1 , 2005, The Journal of Immunology.

[48]  S. Ahn,et al.  Bfl-1 gene expression in breast cancer: its relationship with other prognostic factors. , 2003, Journal of Korean medical science.

[49]  U. Kim,et al.  Bfl-1, a Bcl-2-related gene, is the human homolog of the murine A1, and maps to Chromosome 15q24.3 , 1997, Mammalian Genome.

[50]  A. Karsan,et al.  Endothelial Cell Death Induced by Tumor Necrosis Factor-α Is Inhibited by the Bcl-2 Family Member, A1* , 1996, The Journal of Biological Chemistry.

[51]  A. Kater,et al.  Dichotomy in NF-κB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering , 2010, Oncogene.

[52]  S. Majumdar,et al.  Bfl-1/A1 acts as a negative regulator of autophagy in mycobacteria infected macrophages. , 2011, The international journal of biochemistry & cell biology.

[53]  S. Cheong,et al.  Transcriptional profiling of oral squamous cell carcinoma using formalin-fixed paraffin-embedded samples. , 2010, Oral oncology.

[54]  K. Rajewsky,et al.  Efficiency of RNA Interference in the Mouse Hematopoietic System Varies between Cell Types and Developmental Stages , 2005, Molecular and Cellular Biology.

[55]  R. Haser,et al.  C-terminal Residues Regulate Localization and Function of the Antiapoptotic Protein Bfl-1* , 2009, The Journal of Biological Chemistry.

[56]  Lin Chen,et al.  Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. , 2005, Genes & development.

[57]  D. Kanduc,et al.  Genome‐wide transcriptional profiling in human squamous cell carcinoma of the skin identifies unique tumor‐associated signatures , 2006, The Journal of dermatology.

[58]  T. Grogan,et al.  Transcript profiling in peripheral T-cell lymphoma, not otherwise specified, and diffuse large B-cell lymphoma identifies distinct tumor profile signatures , 2005, Molecular Cancer Therapeutics.

[59]  Derek Y. Chiang,et al.  The landscape of somatic copy-number alteration across human cancers , 2010, Nature.

[60]  K. Roth,et al.  Mcl-1 deficiency results in peri-implantation embryonic lethality. , 2000, Genes & development.

[61]  S. Armstrong,et al.  Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. , 2006, Cancer cell.

[62]  G. Nilsson,et al.  IgE‐receptor activation induces survival and Bfl‐1 expression in human mast cells but not basophils , 2006, Allergy.

[63]  E. Clark,et al.  The CD40-inducible Bcl-2 family member A1 protects B cells from antigen receptor-mediated apoptosis. , 2000, Cellular immunology.

[64]  M. Thangaraju,et al.  Comparison of mammary gland involution between 129S1 and C57BL/6 inbred mouse strains: differential regulation of Bcl2a1, Trp53, Cebpb, and Cebpd expression , 2004, Oncogene.

[65]  I. Park,et al.  Expression of a novel Bcl-2 related gene, Bfl-1, in various human cancers and cancer cell lines. , 1997, Anticancer research.

[66]  C. Gélinas,et al.  Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor , 2005, Cell Death and Differentiation.

[67]  T. Golub,et al.  NFkappaB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes. , 2005, Blood.

[68]  M. Tomayko,et al.  Long-lived B cells are distinguished by elevated expression of A1. , 1998, Journal of immunology.

[69]  H. Varmus,et al.  MYC-induced myeloid leukemogenesis is accelerated by all six members of the antiapoptotic BCL family , 2009, Oncogene.

[70]  I. Berberich,et al.  Overexpression of the antiapoptotic protein A1 promotes the survival of double positive thymocytes awaiting positive selection , 2006, Cell Death and Differentiation.

[71]  N. Takano,et al.  Resistance to cytotoxic chemotherapy-induced apoptosis in side population cells of human oral squamous cell carcinoma cell line Ho-1-N-1. , 2009, International journal of oncology.

[72]  Liming Yang,et al.  Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. , 2002, Immunity.

[73]  M. Walsh,et al.  Eosinophil Adhesion to Cholinergic IMR-32 Cells Protects against Induced Neuronal Apoptosis1 , 2004, The Journal of Immunology.

[74]  John Calvin Reed,et al.  A short Nur77-derived peptide converts Bcl-2 from a protector to a killer. , 2008, Cancer cell.

[75]  G. Cohen,et al.  Bcl-2 inhibitors: small molecules with a big impact on cancer therapy , 2009, Cell Death and Differentiation.

[76]  G. Nilsson,et al.  FcγRI-Mediated Activation of Human Mast Cells Promotes Survival and Induction of the Pro-survival Gene Bfl-1 , 2008, Journal of Clinical Immunology.

[77]  Chien-Ying Liu,et al.  homolog A 1 Perturbation of B-cell development in mice overexpressing the Bcl-2 , 2002 .

[78]  C. Kozak,et al.  The bcl-2 family member, Bcl2a1, maps to mouse Chromosome 9 and human Chromosome 15 , 1997, Mammalian Genome.

[79]  M. Butterworth,et al.  Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. , 2009, Blood.

[80]  Brian J. Smith,et al.  Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. , 2005, Molecular cell.

[81]  Kwang Dong Kim,et al.  Up-regulation of Bfl-1/A1 via NF-kappaB activation in cisplatin-resistant human bladder cancer cell line. , 2004, Cancer letters.

[82]  John Calvin Reed,et al.  Inhibition of Bfl-1 with N-aryl maleimides. , 2010, Bioorganic & medicinal chemistry letters.

[83]  K. Tarte,et al.  The Bcl‐2 family member Bfl‐1/A1 is strongly repressed in normal and malignant plasma cells but is a potent anti‐apoptotic factor for myeloma cells , 2004, British journal of haematology.

[84]  B. Ma,et al.  Bcl-2-related protein A1 is an endogenous and cytokine-stimulated mediator of cytoprotection in hyperoxic acute lung injury. , 2005, The Journal of clinical investigation.

[85]  T. Golub,et al.  Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. , 2004, Blood.

[86]  W. Zong,et al.  The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-κB that blocks TNFα-induced apoptosis , 1999 .

[87]  John Calvin Reed,et al.  Gambogic acid is an antagonist of antiapoptotic Bcl-2 family proteins , 2008, Molecular Cancer Therapeutics.

[88]  J. Tschopp,et al.  The Inflammasomes , 2010, Cell.

[89]  Y. Shim,et al.  Anti-apoptotic role of Bfl-1 in staurosporine-treated B-lymphoblastic cells. , 2000, International journal of hematology.

[90]  Y. Sung,et al.  A novel Bcl-2 related gene, Bfl-1, is overexpressed in stomach cancer and preferentially expressed in bone marrow. , 1995, Oncogene.

[91]  K. Nakayama,et al.  Accelerated Neutrophil Apoptosis in Mice Lacking A1-a, a Subtype of the bcl-2–related A1 Gene , 1998, The Journal of experimental medicine.

[92]  S. Eschrich,et al.  The gene expression profiles of primary and metastatic melanoma yields a transition point of tumor progression and metastasis , 2008, BMC Medical Genomics.

[93]  John Calvin Reed,et al.  Apogossypol derivatives as antagonists of antiapoptotic Bcl-2 family proteins , 2009, Molecular Cancer Therapeutics.

[94]  G. Nilsson,et al.  Essential Role of the Prosurvival bcl-2 Homologue A1 in Mast Cell Survival After Allergic Activation , 2001, The Journal of experimental medicine.

[95]  al. et,et al.  Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice , 1995, Science.

[96]  Yong‐Nyun Kim,et al.  Oxidative stress attenuates Fas-mediated apoptosis in Jurkat T cell line through Bfl-1 induction , 2005, Oncogene.

[97]  S. Levy,et al.  Expression of the Bcl-2 family member A1 is developmentally regulated in T cells. , 1999, International immunology.

[98]  G. Cheng,et al.  Upregulation of Bcl-x and Bfl-1 as a potential mechanism of chemoresistance, which can be overcome by NF-κB inhibition , 2000, Oncogene.

[99]  Margot Thome,et al.  Inhibition of death receptor signals by cellular FLIP , 1997, Nature.

[100]  Roberto Piva,et al.  Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and BCL2A1 as critical target genes. , 2006, The Journal of clinical investigation.

[101]  M. Augustus,et al.  GRS, a novel member of the Bcl-2 gene family, is highly expressed in multiple cancer cell lines and in normal leukocytes , 1997, Oncogene.

[102]  W. Miller,et al.  Combined effect of all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia cells in vitro and in vivo. , 2001, Blood.

[103]  A. Orlofsky,et al.  A1 is a growth-permissive antiapoptotic factor mediating postactivation survival in T cells. , 2003, Blood.

[104]  P. Furth,et al.  Concurrent Pregnancy Retards Mammary Involution: Effects on Apoptosis and Proliferation of the Mammary Epithelium after Forced Weaning of Mice1 , 2002, Biology of reproduction.