Disease relevance of BCL2A1

• AML patients with a normal karyotype showed a higher frequency of BCL2A1 overexpression (P < 0.001) than those with an abnormal karyotype [1].
• Analysis of the pattern of gene expression in cancer cell lines demonstrates GRS is expressed in hematopoietic malignancies and in melanoma [2].

High impact information on BCL2A1

• Here, we describe the induction of the antiapoptotic gene BCL2A1 (A1) as a potential mechanism regulating inhibition of pre-T cell death [3].
• We report the identification of two novel minor histocompatibility antigens (mHAgs), encoded by two separate single nucleotide polymorphisms on a single gene, BCL2A1, and restricted by human histocompatibility leukocyte antigen (HLA)-A*2402 (the most common HLA-A allele in Japanese) and B*4403, respectively [4].
• Of those, only BCL2A1 has been reported to be expressed in hematopoietic cells and possess three nonsynonymous nucleotide changes [4].
• Minigene transfection and epitope reconstitution assays with synthetic peptides identified both HLA-A*2402- and B*4403-restricted mHAg epitopes to be encoded by distinct polymorphisms within BCL2A1 [4].
• We screened a cDNA array and identified the bCL2 family member A1/BFL1 as a new WT1 target gene in 32D cl3 murine myeloblast cells [5].

Biological context of BCL2A1

• Identification of a polymorphic gene, BCL2A1, encoding two novel hematopoietic lineage-specific minor histocompatibility antigens [4].
• Overexpression experiments in REF52 rat fibroblasts showed that BFL-1 conferred increased resistance to apoptosis induced by serum deprivation [6].
• Further examination of BFL-1 and several other anti-apoptotic proteins suggests a more general type of structure based on structural motifs, i.e. a hydrophobic pocket for the binding of proapoptotic proteins, rather than extended sequence homologies [6].
• GRS, a novel member of the Bcl-2 gene family, is highly expressed in multiple cancer cell lines and in normal leukocytes [2].
• Since mutations of the Gln residues located within the BH4 domain appear to confer an extended cell survival activity in the absence of cell proliferation, our results suggest that BFL-1 communicates with both cell proliferation and apoptosis machineries and suggest a link between these two activities [7].

Anatomical context of BCL2A1

• BFL-1 is the smallest member of the BCL-2 family and has been shown to retard apoptosis in various cell lines [6].
• Thus, the role of BCL2A1-specific T cells in differential induction of GVL reactivity and GVHD may depend on the presence of inflammatory responses that may occur during GVHD [8].
• Clinical relevance of a newly identified HLA-A24-restricted minor histocompatibility antigen epitope derived from BCL2A1, ACC-1, in patients receiving HLA genotypically matched unrelated bone marrow transplant [9].

Associations of BCL2A1 with chemical compounds

• Molecular modeling showed that BFL-1 could have a similar core structure as BCL-xL, consisting of seven alpha helices, although both proteins share only the conserved BCL-2 homology domains (BH1 and BH2 domains), but otherwise have very limited sequence homology, particularly in the N-terminal region [6].
• BAX requires the BH3 domain for interaction with BFL-1 [6].
• A unique feature of BFL-1 is the presence of a Gln-rich N-terminal region that overlaps with the BH4 domain [7].
• Elemental analysis of solids with the Hbpa ligand have indicated better complexation for synthesis in toluene, where 74% of the iron atoms were coordinated by the ligand, against 37% for the synthesis in methanol [10].
• We report the encapsulation of iron and copper metallocomplexes with the ligand (2-hydroxybenzyl)(2-methylpyridyl)amine, Hbpa, and iron complexes with the ligand N,N'-bis(2-hydroxybenzyl)-N,N'-bis(2-methylpyridyl) ethylenediamine, H(2)bbpen [10].

Physical interactions of BCL2A1

• We demonstrated in the yeast two-hybrid system that BFL-1 interacts strongly with human BAX but is not able to form homodimers nor to interact with human BCL-2 or BCL-xL [6].

Other interactions of BCL2A1

• Structural basis of BFL-1 for its interaction with BAX and its anti-apoptotic action in mammalian and yeast cells [6].
• A. phagocytophilum infection also altered the apoptotic program of NB4 cells and resulted in increased transcription of antiapoptotic genes (MCL1 and BFL1) [11].
• Recently, the HLA-A24-restricted mHag ACC-1 and the HLA-B44-restricted mHag ACC-2 encoded by separate polymorphisms within the BCL2A1 gene were characterized [8].
• We recently identified a new mHA epitope, termed ACC-1, which is presented by HLA-A*2402 and encoded by BCL2A1, whose expression is restricted to haematopoietic cells including leukaemic cells [9].
• The FGF-4 gene was truncated by DNA rearrangement with a novel gene named GRS [2].

Analytical, diagnostic and therapeutic context of BCL2A1

• Up-regulated expression in nonhematopoietic tissues of the BCL2A1-derived minor histocompatibility antigens in response to inflammatory cytokines: relevance for allogeneic immunotherapy of leukemia [8].
• The antiapoptotic gene A1/BFL1 is a WT1 target gene that mediates granulocytic differentiation and resistance to chemotherapy [5].
• For the immobilization with the H(2)bbpen ligand in toluene it was observed that 46% of the iron atoms are coordinated, showing that the diffusion of the small ligand Hbpa through the zeolite cage was facilitated [10].

References