Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: PAX5
Cytogenetic location: 9p13.2 Genomic coordinates (GRCh38): 9:36,833,269-37,034,268 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p13.2 | {Leukemia, acute lymphoblastic, susceptibility to, 3} | 615545 | 3 |
PAX5 is a transcription factor essential for B-cell differentiation that activates B cell-specific genes and represses genes specific for other hematopoietic lineages (summary by Kawamata et al., 2012).
At least 8 paired box genes, including Pax5, have been identified in the mouse (Walther et al., 1991). B-cell lineage-specific activator protein (BSAP) was first identified as a transcription factor that is expressed at early, but not late, stages of B-cell differentiation. By biochemical purification and cDNA cloning, Adams et al. (1992) demonstrated that BSAP belongs to the family of paired domain proteins. Specifically, BSAP is encoded by the PAX5 gene, which is highly conserved between human and mouse. An intact paired domain was shown to be both necessary and sufficient for DNA binding of BSAP. During embryogenesis, the BSAP gene is transiently expressed in the mesencephalon and spinal cord with a spatial and temporal expression pattern that is distinct from that of other PAX genes in the developing CNS. Later, expression of the BSAP gene shifts to the fetal liver where it correlates with the onset of B-cell lymphopoiesis. BSAP expression persists in B lymphocytes and is also seen in the testis of the adult mouse. Thus, the transcription factor BSAP may play an important role not only in B-cell differentiation but also in neural development and spermatogenesis.
Li et al. (2015) reported that PAX5 is expressed in almost all cell types. Using Western blot analysis, they confirmed that PAX5 was expressed in primary human endothelial cells, as well as in a human endothelial cell line.
Studying the expression of individual mouse Pax5 alleles at the single-cell level, Nutt et al. (1999) demonstrated that Pax5 is subject to allele-specific regulation during B-lymphopoiesis. Pax5 is predominantly transcribed from only 1 allele in early progenitors and mature B cells, whereas it switches to biallelic transcription in immature B cells. The allele-specific regulation of Pax5 is stochastic, reversible, and independent of parental origin, and it correlates with synchronous replication, in contrast with imprinted and other monoallelically expressed genes. Consequently, B-lymphoid tissues are mosaics with respect to the transcribed Pax5 allele, and thus mutation of 1 allele in heterozygous mice results in deletion of the cell population expressing the mutant allele. The authors concluded that similar allele-specific regulation may be a common mechanism causing the haploinsufficiency and frequent association of other PAX genes with human disease.
Rolink et al. (1999) studied mechanisms controlling the commitment of hematopoietic progenitors to the B-lymphoid lineages. The observations that mice deficient in E2A (147141) and EBF (164343) lack B-lineage cells have implicated these 2 transcription factors in the commitment process. Moreover, the expression of genes encoding components of the rearrangement machinery (RAG1, 179615; RAG2, 179616; DNTT, 187410) or pre-B cell receptor has been considered to indicate B-lineage commitment. All these genes, including E2A and EBF, are expressed in pro-B cells lacking the transcription factor Pax5. Rolink et al. (1999) demonstrated that cloned Pax5-deficient pro-B cells transferred into Rag2-deficient mice provide long-term reconstitution of the thymus and give rise to mature T cells expressing alpha/beta-T-cell receptors. The bone marrow of these mice contains a population of cells of Pax5 -/- origin with the same phenotype as the donor pro-B cells. When transferred into secondary recipients, these Pax5 -/- pro-B cells again home to the bone marrow and reconstitute the thymus. Hence, B-lineage commitment is determined neither by immunoglobulin DJ rearrangement nor by the expression of E2A, EBF, or pre-B cell receptor antigens. Instead, Rolink et al. (1999) concluded that their data implicated PAX5 in the control of B-lineage commitment.
Nutt et al. (1999) demonstrated that pro-B cells lacking Pax5 are incapable of in vitro B-cell differentiation unless Pax5 expression is restored by retroviral transduction. Pax5 -/- pro-B cells are not restricted in their lineage fate, as stimulation with appropriate cytokines induces them to differentiate into functional macrophages, osteoclasts, dendritic cells, granulocytes, and natural killer cells. As expected for a clonogenic hematopoietic progenitor with lymphomyeloid developmental potential, the Pax5 -/- pro-B cell expresses genes of different lineage-affiliated programs, and restoration of Pax5 activity represses this lineage-promiscuous transcription. Pax5 therefore plays an essential role in B-lineage commitment by suppressing alternative lineage choices. Differentiation of the hematopoietic stem cell into distinct blood cell types was thought to progress through intermediate progenitor cells with restricted developmental potential. This view of hematopoiesis was challenged by the findings of Nutt et al. (1999) that the Pax5 -/- pro-B cell possesses, at least under in vitro conditions, a broad, developmental potential similar to that of the hematopoietic stem cell itself. However, Pax5 -/- pro-B cells are unable to differentiate along the erythroid and megakaryocytic lineages, and cannot reconstitute the entire hematopoietic system under transplantation experiments. Therefore, Nutt et al. (1999) concluded that the Pax5 -/- pro-B cell must be classified as a hematopoietic progenitor cell with broad lymphoid and myeloid differentiation potential. Nutt et al. (1999) also concluded that their data supported the notion that B-lineage commitment is a stochastic rather than a deterministic process.
Mikkola et al. (2002) extended the findings of Nutt et al. (1999) using conditional Pax5 inactivation with the Cre-loxP system. They established that multipotent hemopoietic progenitors can be established from wildtype pro-B cells. Mikkola et al. (2002) proposed that strategies to downregulate PAX5 expression in donor pro-B cells could be used to restore T-cell development in patients with acquired immunodeficiency syndrome (AIDS) or inherited immunodeficiency syndromes.
Johnson et al. (2004) found that methylation of histone-3 (see 602810) at lys9 (H3-K9), a mark of inactive chromatin, was present in the VH locus of Ig in non-B cells but was absent in B cells. Removal of H3-K9 methylation required expression of Pax5. Johnson et al. (2004) proposed that Pax5-mediated removal of H3-K9 methylation in the VH locus makes VH genes accessible for VH-to-DJH recombination and allows for further B-cell development.
In mouse pro-B cells, Holmes et al. (2006) found that repression of Flt3 (136351) by Pax5 was crucial for B-cell lineage commitment.
Nera et al. (2006) established a Pax5-deficient chicken B-cell line and found that these cells exhibited slower growth, decreased surface IgM expression, and complete loss of B-cell receptor (BCR) signaling. Moreover, expression of the plasmacytic transcription factors Blimp1 (PRDM1; 603423) and Xbp1 (194355) was upregulated, IgM secretion was elevated, and Bcl6 (109565) expression was diminished in Pax5-deficient B cells. Nera et al. (2006) concluded that PAX5 downregulation promotes differentiation of B cells to plasma cells.
Cobaleda et al. (2007) demonstrated that conditional Pax5 deletion in mice allowed mature B cells from peripheral lymphoid organs to dedifferentiate in vivo back to early uncommitted progenitors in the bone marrow, which rescued T lymphopoiesis in the thymus of T cell-deficient mice. These B cell-derived T lymphocytes carried not only immunoglobulin heavy and light chain gene rearrangements but also participated as functional T cells in immune reactions. Mice lacking Pax5 in mature B cells also developed aggressive lymphomas, which were identified by their gene expression profile as progenitor cell tumors. Hence, Cobaleda et al. (2007) concluded that the complete loss of Pax5 in late B cells could initiate lymphoma development and uncovered an extraordinary plasticity of mature peripheral B cells despite their advanced differentiation stage.
Cozma et al. (2007) reconstituted mouse B-lymphoma cell lines that had spontaneously silenced Pax5 with a Pax5-tamoxifen receptor fusion protein and observed increased hormone-dependent neoplastic growth. Expression of dominant-negative murine Pax5 in murine lymphomas or knockdown of PAX5 in human lymphomas reduced cell expansion. Expression profiling revealed that Pax5 was required to maintain expression of several components of B-cell receptor (BCR) signaling, including the immunoreceptor tyrosine-based activation motif (ITAM)-containing Cd79a (112205). On the other hand, Pax5 expression repressed the BCR signaling inhibitors Cd22 (107266) and Pirb (LILRB3; 604820), which are ITAM antagonists. Human B-cell lymphomas consistently expressed phosphorylated BLNK (604515), an activated BCR adaptor protein. Cozma et al. (2007) concluded that PAX5 stimulation of neoplastic growth occurs through BCR and can be inhibited both genetically and pharmacologically.
Mora-Lopez et al. (2007) identified a conserved PAX5-binding element within exon 1 of the human PRDM1 gene, which encodes a master regulator of plasma cell differentiation that represses the PAX5 gene. Chromatin immunoprecipitation assays confirmed binding of PAX5 to this element, and PAX5 binding repressed PRDM1 activity in a reporter assay. Mora-Lopez et al. (2007) concluded that PAX5 negatively regulates PRDM1 expression in an autoregulatory negative feedback loop.
Using reporter gene assays and chromatin immunoprecipitation analysis, Li et al. (2015) found that PAX5 upregulated expression of MICAL3 (608882) in human endothelial cells. PAX5 simultaneously upregulated expression of the precursor for microRNA-648 (MIR648; 616205), which originates from intron 1 of MICAL3. PAX5 bound 3 of 7 putative binding sites in the distal promoter of MICAL3. Overexpression and knockdown studies confirmed that PAX5 simultaneously upregulated expression of MICAL3 and MIR648.
Lesions in the PAX5 and IKZF1 (602023) genes, encoding B-lymphoid transcription factors, occur in over 80% of cases of pre-B-cell acute lymphoblastic leukemia (ALL; see 613065). By combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, Chan et al. (2017) identified a novel B-lymphoid program for transcriptional repression of glucose and energy supply. The metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK (see 602739). Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a nonpermissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (138040), encoding the glucocorticoid receptor, TXNIP (605051), encoding a glucose feedback sensor, and CNR2 (605051), encoding a cannabinoid receptor, as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukemic transformation. Conversely, pharmacologic TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2, and AMPK as potential therapeutic targets. Furthermore, these results provided a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation.
Generation of a diverse antibody repertoire requires participation of all V genes in V(D)J recombination, which depends on contraction of the immunoglobulin heavy chain (IGH; see 147100) locus by PAX5. Hill et al. (2020) demonstrated that loop extrusion across the entire mouse Igh locus caused Igh contraction. Pax5 repressed expression of the cohesin release factor Wapl (610754) specifically in pro-B and pre-B cells, facilitating extended loop extrusion by increasing the residence time of cohesin on chromatin. Pax5 mediated transcriptional repression of Wapl through a single Pax5-binding site by recruiting polycomb repressive complex-2 (PRC2; see 601573) to induce bivalent chromatin at the Wapl promoter. Reduced Wapl expression caused global alterations in chromosome architecture, indicating that the potential to recombine all V genes entails structural changes of the entire genome in pro-B cells.
Pilz et al. (1993) used a mouse cDNA probe for Pax5 to map the human homolog to chromosome 9 in somatic cell hybrids. The gene was not present in a hybrid containing only the long arm of chromosome 9, indicating that PAX5 maps to 9p. The homologous gene maps to mouse chromosome 4. By analysis of somatic cell hybrids and by fluorescence in situ hybridization, Stapleton et al. (1993) assigned the PAX5 gene to 9p13. Vorechovsky et al. (1995) refined the map location of the PAX5 locus to a 9-cM region between D9S263 and D9S200 at 9p21.1-p13.3.
Since the PAX5 gene encodes a B-cell-specific activator protein (BSAP) that binds to promoters of the CD19 gene, B cell-specific tyrosine kinase gene BLK (191305), and to regulatory regions of the immunoglobulin heavy chain locus, including sequences implicated in Ig class switching, Vorechovsky et al. (1995) investigated a possible link between PAX5 and human primary immunodeficiencies by combined linkage and direct mutation analyses of this gene in candidate human phenotypes. However, no relationship to immunodeficiency was demonstrated.
In addition to immunoglobulin V genes, the 5-prime sequences of BCL6 and FAS (TNFRSF6; 134637) are mutated in normal germinal center B lymphocytes. Genomic instability promotes tumorigenesis through defective chromosome segregation and DNA mismatch repair inactivation. By screening 18 loci for mutations, Pasqualucci et al. (2001) identified changes in the germline sequences of PIM1 (164960), MYC (190080), ARHH (602037), and/or PAX5, in addition to BCL6, in a majority of diffuse large cell lymphomas (DLCLs; see 601889). No mutations in PIM1, MYC, ARHH, and PAX5 were detected in germinal-center lymphocytes, naive B cells, or B-cell malignancies other than DLCLs. PAX5 mutations, which were observed in 57% of DLCLs, were identified downstream of both transcription sites, predominantly in noncoding sequences around exon 1B. FISH analysis indicated that hypermutation in these genes is not due to chromosomal translocation, as seen in Burkitt lymphoma (113970). Chromosomal translocation, however, may be an outcome of hypermutation. Specific features of the hypermutation process, including the predominance of single nucleotide substitutions with occasional deletions or duplications, a preference for transitions over transversions, and a specific motif targeting RGYW, were recognizable in each of the hypermutated loci. Pasqualucci et al. (2001) proposed that aberrant hypermutation of regulatory and coding sequences of genes that do not represent physiologic targets may provide the basis for DLCL pathogenesis and explain its phenotypic and clinical heterogeneity. This hypermutation malfunction is unlikely to be due to defective DNA mismatch repair and does not appear to involve activation-induced deaminase (AICDA; 605257)
Mullighan et al. (2007) performed a genomewide analysis of leukemic cells from 242 pediatric ALL (613065) patients using high resolution single-nucleotide polymorphism (SNP) arrays and genomic DNA sequencing. Their analyses revealed deletion, amplification, point mutation, and structural rearrangement in genes encoding principal regulators of B-lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (147141), EBF1 (164343), LEF1 (153245), IKZF1 (603023), and IKZF3 (606221). Mullighan et al. (2007) concluded that direct disruption of pathways controlling B cell development and differentiation contribute to B-progenitor ALL pathogenesis. Moreover, these data demonstrated the power of high resolution genomewide approaches to identify new molecular lesions in cancer.
Susceptibility to Acute Lymphoblastic Leukemia 3
In affected members of 2 unrelated families with childhood onset of B-cell acute lymphoblastic leukemia-3 (ALL3; 615545), Shah et al. (2013) identified a heterozygous germline mutation in the PAX5 gene (G183S; 167414.0001). The mutation was found by exome sequencing and was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases. One of the families was of Puerto Rican descent and the other was of African American descent. The mutation segregated with the disorder, but there were several unaffected obligate carriers, suggesting incomplete penetrance. All available leukemic samples showed loss of chromosome 9p either through the formation of an isochromosome (i(9)(q10)) or dicentric chromosomes involving 9p, both resulting in loss of the wildtype PAX5 allele and retention of the mutant allele. Haplotype analysis suggested that the mutation arose independently in each family. In vitro functional expression studies showed that the mutant G183S protein had normal subcellular localization, but reduced transcriptional activation compared to wildtype, indicating partial loss of function. Transcriptional profiling of mouse cells expressing the mutation showed reduced expression of genes activated by PAX5 in pro-B cells and mature B cells. However, the effect of the G183S mutant was not as severe as that observed for complete loss-of-function PAX5 alleles. The findings suggested that this partial hypomorphic allele is tolerated as a germline allele and that additional somatic genetic events further reducing PAX5 activity are required to establish the leukemic clone. Sequencing of the PAX5 gene in samples from 44 additional patients with sporadic pre-B-ALL who had i(9)(q10) or dic(9;v) aberrations found that 2 patients had somatic mutations affecting codon 183 (G183S and G183V, respectively), and 10 had other PAX5 mutations. There was a significantly higher frequency of somatic PAX5 mutations among a cohort of B-ALL patients with isochromosomal or dicentric aberrations of chromosome 9 compared to those without these genetic aberrations, suggesting that PAX5 mutations frequently cooccur with loss of 9p. No germline PAX5 mutations were detected in 39 families with a history of 2 or more cases of cancer, although 1 familial case had harbored a somatic dic(9;20)(p11;q11.1) alteration and a somatic PAX5 variant.
Using integrated genomic analysis of leukemic cells from 1,988 childhood and adult cases of B-progenitor acute lymphoblastic leukemia (B-ALL), Gu et al. (2019) described a revised taxonomy of B-ALL incorporating 23 subtypes. Two subtypes were characterized by distinct gene expression profiles and different types of PAX5 alterations. One, PAX5alt (PAX5-altered), accounted for 148 (7.4%) of cases and had diverse PAX5 alterations including rearrangements, intragenic amplifications, or mutations. Children in this subtype were more commonly classified as high risk rather than standard risk (63 vs 17, respectively) according to NCI criteria. In the PAX5alt group, 57 cases (38.5%) harbored PAX5 rearrangements involving 24 partner genes, the most common of which was PAX5-ETV6 (600618) in 19 cases. Forty-six (31%) of PAX5alt group cases harbored nonsilent PAX5 sequence mutations, compared with 79 (4.4%) of other B-ALL cases. A distinct second PAX5 subtype was defined by the pro80 to arg variant (P80R; 615545.0002), which was present in all 44 cases compared with 4 of 1,944 other B-ALL cases (0.2%). In 30 cases, the P80R mutation was hemizygous or homozygous, owing to deletion of the wildtype PAX5 allele or copy-neutral loss of heterozygosity. Of the remaining 14 cases with heterozygous PAX5 P80R-encoding alterations, 7 harbored a second frameshift, 2 a nonsense, and 4 a deleterious missense PAX5 mutation. The 4 of remaining 1,944 cases that harbored the P80R mutation were heterozygous with preservation of a wildtype PAX5 allele and had similar gene expression profiles to those of other subtypes, in agreement that biallelic PAX5 mutations, including P80R, are a hallmark of this subtype.
The PAX5 gene is located in the 9p13 region, which is involved in t(9;14)(p13;q32) translocations recurring in small lymphocytic lymphomas of the plasmacytoid subtype and in derived large cell lymphomas. Ohno et al. (1990) showed that in a diffuse large cell lymphoma (KIS-1) with a translocation, the immunoglobulin heavy-chain (IgH) locus on 14q32 is juxtaposed to 9p13 sequences of unknown function. Busslinger et al. (1996) showed that the KIS-1 translocation breakpoint is located 1,807 bp upstream of exon 1A of PAX5, thus bringing the potent E-mu enhancer of the IgH gene into close proximity with the PAX5 promoters. The data suggested to them that deregulation of PAX5 gene transcription by the t(9;14) translocation contributes to the pathogenesis of small lymphocytic lymphomas with plasmacytoid differentiation.
Kawamata et al. (2012) stated that in-frame fusion between exon 5 of PAX5 and exon 8 of C20ORF112 (NOL4L; 618893) results in an ALL-associated fusion protein, PAX5-C20S, that is a potent dominant-negative suppressor of wildtype PAX5. Kawamata et al. (2012) found that PAX5-C20S formed a tetramer through mediation by the putative C-terminal alpha-helical region of C20ORF112. Tetramerization of the PAX5 DNA-binding domain led to extremely stable chromatin binding. PAX5-C20S bound DNA with 10-fold higher affinity than monomeric PAX5, leading to dominant-negative suppression of wildtype PAX5 activity through binding competition.
Pax5 -/- mice lose all B-cell development beyond the early pro-B cell stage, are severely runted, and die in the early postnatal period (Urbanek et al., 1994). By histomorphometric and microscopy analyses, Horowitz et al. (2004) found that Pax5 -/- mice, but not other B-cell-deficient mice, showed a 60% reduction in bone volume. The osteopenia was accounted for by an increase of more than 100% in the number of osteoclasts in bone. Spleen cells, but not bone marrow cells, produced significantly higher numbers of monocyte osteoclast precursors. Horowitz et al. (2004) concluded that B cells and PAX5 have roles in osteoclast development.
In affected members of 2 unrelated families with childhood onset of B-cell acute lymphoblastic leukemia-3 (ALL3; 615545), Shah et al. (2013) identified a heterozygous germline c.547G-A transition in the PAX5 gene, resulting in a gly183-to-ser (G183S) substitution in the octapeptide domain. The mutation was found by exome sequencing and was not present in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases. One of the families was of Puerto Rican descent and the other was of African American descent. The mutation segregated with the disorder, but there were several unaffected obligate carriers, suggesting incomplete penetrance. All available leukemic samples showed loss of chromosome 9p through the formation of an isochromosome of 9q (i(9)(q10)) or dicentric chromosomes, both resulting in loss of the wildtype PAX5 allele and retention of the mutant allele. Haplotype analysis suggested that the mutation arose independently in each family. In vitro functional expression studies showed that the mutant G183S protein had normal subcellular localization, but reduced transcriptional activation compared to wildtype, indicating partial loss of function. Transcriptional profiling of mouse cells expressing the mutation showed reduced expression of genes activated by PAX5 in pro-B cells and mature B cells. However, the effect of the G183S mutant was not as severe as that observed for complete loss-of-function alleles. The findings suggested that this partial hypomorphic allele is tolerated as a germline allele and that additional somatic genetic events further reducing PAX5 activity are required to establish the leukemic clone. No germline PAX5 mutations were detected in 39 families with a history of 2 or more cases of cancer, although 1 familial case of ALL harbored a somatic dic(9;20)(p11;q11.1) alteration and a somatic PAX5 variant.
In a revised taxonomy of B-ALL developed through integrated genomic analysis of leukemic cells from 1,988 childhood and adult cases of B-cell acute lymphoblastic leukemia (B-ALL), Gu et al. (2019) identified 44 cases with a pro80-to-arg (P80R) alteration in PAX5 as well as a distinct gene expression profile. In 30 cases, the P80R mutation was hemizygous or homozygous, owing to deletion of the wildtype PAX5 allele or copy-neutral loss of heterozygosity. Of the remaining 14 cases with heterozygous PAX5 P80R-encoding alterations, 7 harbored a second frameshift, 2 a nonsense, and 4 a deleterious missense PAX5 mutation. The 4 of remaining 1,944 cases that harbored the P80R mutation were heterozygous with preservation of a wildtype PAX5 allele and had similar gene expression profiles to those of other subtypes, in agreement that biallelic PAX5 mutations, including P80R, are a hallmark of this subtype. To examine the effects of PAX5 P80R on B cell maturation, Gu et al. (2019) expressed wildtype PAX5 and PAX5 carrying P80R or another missense mutation in Pax5-/- lineage-depleted bone marrow cells. Only PAX5 P80R expression led to a block in differentiation at the pre-pro-B stage of B cell maturation. Heterozygous and homozygous knockin PAX5 P80R mice developed B progenitor leukemia with median latencies of 160 and 83 days, respectively, whereas a gly183-to-ser (G183S; 167414.0001) variant did not induce leukemia. Gu et al. (2019) concluded that PAX5 P80R drives B lymphoid leukemogenesis.
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