Transcription factor BACH2 is transcriptionally regulated by the BCR/ABL oncogene

Abstract

Expression of BCR/ABL, a constitutively active tyrosine kinase, is a primary event in the pathogenesis of chronic myeloid leukemia (CML) and Ph-positive acute lymphoblastic leukemia (Ph+ALL). Inhibition of the BCR/ABL kinase activity in the BV173 CML cell line with STI571 resulted in a significant overexpression of a 10-kb novel mRNA, found to be the human ortholog of the murine Bach2, a B-cell-specific transcription factor. The human BACH2 cDNA is >9,120 bp long and includes an open reading frame of 2,526 bp encoding a protein with a basic leucine zipper (bZip) and a BTB/POZ domain, mediating DNA-binding and heterodimerization. BACH2 was consistently upregulated (2-10-fold) in all 10 Ph+ lymphoid lines tested following BCR/ABL inhibition. In CML myeloid cell lines (n = 8) and BCR/ABL-negative lines (n = 6), BACH2 was either undetectable by Northern blotting or did not change in response to STI571, suggesting that BACH2 repression by BCR/ABL may be specifically relevant to lymphoid transformation. Quantitative RT/PCR revealed a significantly lower level of BACH2 expression in leukocytes from patients with CML (n = 24) as compared to normal individuals (n = 23) (P < 0.0005). Moreover, CD34+ cells treated in vitro with STI571 exhibited a consistent upregulation of BACH2 in 8 of 10 CMLs but in none of the 9 normal individuals tested. Transcription regulation of BACH2 in BCR/ABL-positive cells was exerted via the MEK pathways, as shown by their responses to the U0126-specific inhibitor. Radiation hybrid mapping and FISH revealed that BACH2 is located on chromosome 6, band q15, a region frequently associated with deletions in ALL and non-Hodgkin's lymphoma, suggesting its possible role as a tumor suppressor gene. However, no rearrangement or loss of signal was observed by Southern blotting in 34 lymphomas, 10 B-cell ALLs, or seven reactive lymph nodes. The pattern of BACH2 expression in BCR/ABL-positive cells suggests that transcriptional repression by this regulator is impaired in CML and may contribute to the emergence of lymphoid blast crisis.

Activation of Maf/AP-1 Repressor Bach2 by Oxidative Stress Promotes Apoptosis and Its Interaction with Promyelocytic Leukemia Nuclear Bodies

“…The involvement of Bach2 in apoptosis agrees with previous observations that Bach2 is a candidate tumor suppressor of B-cell lymphoma (31). Further, inhibition of BCR/ABL kinase activity using STI571 in chronic myeloid leukemia cell lines and CD34 ϩ cells from chronic myeloid leukemia patients during a lymphoid crisis, induces BACH2 expression (57). Because the most striking consequence of suppressing BCR/ABL tyrosine kinase activity is the inhibition of proliferation and subsequent induction of apoptosis (44,58,59), these observations also imply a pro-apoptotic role for Bach2.…”

Gene Expression Signature of Human Cancer Cell Lines Treated with the Ras Inhibitor Salirasib (S-Farnesylthiosalicylic Acid)

“…Inhibition of BCR/ABL by Gleevec indeed induced up-regulation of Bach2 at both the transcript and the protein levels. Similarly, both U0126 (MAPK/ ERK kinase inhibitor) and LY294002 (PI3K inhibitor) up-regulated Bach2 expression in BCR/ABL-positive lines (46). Other studies showed that Bach2 is induced by oxidative stress (47).…”

“…Another interesting reported finding was that the transcription and protein expression of Bach2 is negatively regulated by the BCR/ABL oncogene, which also activates Ras and its signaling in BCR/ABL-positive leukemia cells (46). Inhibition of BCR/ABL by Gleevec indeed induced up-regulation of Bach2 at both the transcript and the protein levels.…”

Genomic deletion of MAP3K7 at 6q12-22 is associated with early PSA recurrence in prostate cancer and absence of TMPRSS2:ERG fusions

“…The five genes located within this area (MDN1, CASP8AP2, GJA10, BACH2 and MAP3K7) are also part of the minimal commonly deleted region founding our study. All of these five genes have a known or suggested tumor suppressor function, 3,5,6,[28][29][30] but accumulating evidence suggested MAP3K7 as the 6q15 tumor suppressor in prostate cancer. [2][3][4][5][6] MAP3K7 was the only one of the five genes, which was found expressed at significantly lower levels in tumor cells as compared with normal prostate.…”