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|CSC-SC001294||Panoply™ Human BACH2 Over-expressing Stable Cell Line||Inquiry|
BACH2, a B-cell–specific transcription factor that is abundantly expressed in lymphocytes of B-cell lineage and B-cell lymphoma cell lines, and plays an important role in B cells development and oxidative stress-induced apoptosis.
BACH2 Regulates Aberrant Activation of B cell in Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune disease related to multiple organs and systems including brain, heart, kidneys, serosal surfaces, blood cells, skin and joints. The pathogenesis of SLE is very complicated. Genome-wide association studies indicate that BACH2 is a susceptible gene for SLE.
BACH2 is a transcriptional target of BCR-ABL, and proposes an inhibitory effect of BCR-ABL on BACH2 expression. Similarly, in a recent study, it was also found that BCR-ABL overexpression in B cells from SLE patients inhibited BACH2 expression. In addition, BCR-ABL dramatically eliminates the effects of BACH2 on B cells, functioning as an anti-apoptotic factor in SLE. In addition to the repressive effect of BCR-ABL on BACH2 expression. Yoshida et al. also reported the inhibitory effect of BACH2 on nuclear translocation via serine phosphorylation of the PI-3K/S6K pathway. BCR-ABL phosphorylates several substrates that activate various signaling pathways, such as signal transducer and activator of transcription (STAT5), Janus kinase 2 (Jak-2), extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK), PI3K, and others. Previous work has determined that BCR-ABL phosphorylates BACH2 by PI3K/Akt in B- lymphocytes and can be reversed after treatment with LY294002 (PI3K inhibitor). Besides, it has been reported that mature B cells depending on the survival signals delivered to the cells by their antigen receptor (BCR), and play an important role in cell proliferation, development, differentiation, and apoptosis through initiating their downstream PI3K/Akt signaling pathway. Also, several studies have focused on the biological study of this pathway, Zheng wei et al. belive that BCR-ABL may inhibit the nuclear translocation of BACH2 through serine phosphorylation of the PI3K pathway in SLE.
The Critical Role of BACH2 in Regulating Type 2 Chronic Airway Inflammation
Although BACH2 plays an important role in regulating Th2 cell differentiation and type 2 immune responses, the underlying molecular mechanisms remain unclear. Current studies demonstrate that BACH2 associates with Batf (basic leucine zipper transcription factor ATF-like) transcription factors family and binds to the regulatory regions of the Th2 cytokine gene loci. The BACH2–Batf complex antagonizes the recruitment of the interferon regulatory factor 4 (Irf4)-containing Batf complex to activator protein 1 (AP-1) motifs in the Th2 cytokine gene locus and suppresses Th2 cytokine production and/or Th2 cell differentiation. The deletion of Batf ameliorated the spontaneous development of type 2 airway inflammation that is found in mice with BACH2 deficiency specifically in T cells. Interestingly, BACH2 regulates Batf and Batf3 expression via two distinct pathways. First, the BACH2–Batf complex directly binds to the Batf and Batf3 gene loci and reduces transcription by interfering with the Batf–Irf4 complex. Second, BACH2 suppresses interleukin 4 (IL-4)-induced augmentation of Batf and Batf3 expression through the regulation of IL-4 production. These findings suggest that IL-4 and Batf family transcription factors form a positive feedback amplification loop to induce Th2 cell differentiation and that BACH2-Batf interactions block the formation of this amplification loop. Furthermore, studies have found that the reductions of BACH2 confer an innate immunological function on CD4 T cells to induce antigen-independent cytokine production. Some BACH2-deficient lung CD4 T cells showed characteristic features similar to pathogenic Th2 cells, including IL-33 receptor expression and IL-33-dependent Th2 cytokine production. These results suggest a critical role of Bach2 in regulating Th2 cell differentiation and the subsequent onset of chronic type 2 inflammation.
BCL6/BACH2 Axis in Acute Lymphoblastic Leukemia
B-Cell CLL/Lymphoma 6 (BCL6) is a proto-oncogene that is highly expressed in acute lymphoblastic leukemia (ALL). BACH2 is a transcriptional suppressor. BACH2–BCL6 balance controls the selection of pre-B cell receptor checkpoint by regulating p53 expression. Recent study have found that Ikaros, a tumor suppressor encoded by IKZF1, directly binds to both the BCL6 and BACH2 promoters where it suppresses BCL6 and promotes BACH2 expression in B-cell ALL (B-ALL) cells. Casein kinase 2 (CK2) inhibitors increase Ikaros function, thereby inhibiting BCL6 and promoting BACH2 expression in an Ikaros-dependent manner. Compared with normal bone marrow controls, BCL6 expression is elevated and BACH2 expression is decreased in B-ALL patients. High BCL6 and low BACH2 expression are associated with high leukemic cell proliferation, unfavorable clinical and laboratory features, and inferior outcomes. Moreover, IKZF1 deletion is associated with high BCL6 and low BACH2 expression in B-ALL patients. CK2 inhibitors increase Ikaros binding to the promoter of BCL6 and BACH2 and suppress BCL6, while promoting BACH2 expression in primary B-ALL cells. Our data indicate that Ikaros regulates expression of the BCL6/BACH2 axis in B-ALL. High BCL6 and low BACH2 expression are associated with Ikaros dysregulation and have a potential effect on the development of B-ALL.
Fig 1. Model for Ikaros regulation on BCL6-BACH2 axis expression. Ikaros suppresses BCL6 but promotes BACH2 expression by binding to their promoter regions, which will result in the arrest of leukemia cells by induction of apoptosis (Ge Z, Zhou X, Gu Y, et al. Oncotarget. 2017).
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