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Transcription factor BACH2 is transcriptionally regulated by the BCR/ABL oncogene
Author(s) -
Vieira Sara A.D.,
Deininger Michael W.N.,
Sorour Amani,
Sinclair Paul,
Foroni Letizia,
Goldman John M.,
Melo Junia V.
Publication year - 2001
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.1200
Subject(s) - abl , breakpoint cluster region , biology , cancer research , transcription factor , myeloid leukemia , microbiology and biotechnology , tyrosine kinase , philadelphia chromosome , oncogene , downregulation and upregulation , cell cycle , chromosomal translocation , cell , signal transduction , gene , genetics
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. © 2001 Wiley‐Liss, Inc.