title: 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.
authors.affiliation: Department of Haematology, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
authors.forename: S A
authors.initials: SA
authors.lastname: Vieira
authors.forename: M W
authors.initials: MW
authors.lastname: Deininger
authors.forename: A
authors.initials: A
authors.lastname: Sorour
authors.forename: P
authors.initials: P
authors.lastname: Sinclair
authors.forename: L
authors.initials: L
authors.lastname: Foroni
authors.forename: J M
authors.initials: JM
authors.lastname: Goldman
authors.forename: J V
authors.initials: JV
authors.lastname: Melo
mesh_terms: D000328:Adult; D050976:Basic-Leucine Zipper Transcription Factors; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D003001:Cloning, Molecular; D005091:Exons; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement / Q000235:genetics; D016313:Genes, abl / Q000502:physiology*; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007438:Introns; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism; D008232:Lymphoproliferative Disorders / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: C491123:BACH2 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D014157:Transcription Factors; D016044:Fusion Proteins, bcr-abl