Nuclear positioning of the BACH2 gene in BCR-ABL positive leukemic cells.
BACH2 is a B-cell-specific transcription repressor and is also know as a tumor suppressor in B cell malignancy. Expression of BACH2 is induced in BCR-ABL positive lymphoid cell lines including BV173 by imatinib, a molecular targeting agent for the treatment of chronic myeloid leukemia (CML). Here we show that the activity of the BACH2 gene is related to the nuclear positioning of the gene loci. We examined the spatial association of the BACH2 gene with the centromeric heterochromatin, a transcriptionally repressive subnuclear compartment, by comparing cells with low (BV173 and K562) and high (NAMALWA) levels of BACH2 mRNA. The BACH2 gene was located closer to the centromeric heterochromatin in BV173 and K562 cells as compared to NAMALWA cells. In BV173 cells, the BACH2-centromere distance increased after imatinib treatment to levels similar to those in NAMALWA cells. We also found that diethylmaleate, an oxidative stressor, enhanced the antiproliferative effect of imatinib in only BV173 cells. Since BACH2 induces apoptosis by oxidative stress, these observations suggest that down-regulation of the BACH2 gene through the interaction with centromeric heterochromatin would take part in leukomogenesis of BCR-ABL positive lymphoid leukemia.
Ono
Atsushi
A
Department of Cellular Biology, Research Institute for Radiation Biology and Medicine, Graduate school of Biomedical Science, Hiroshima University, Hiroshima, Japan.
Kono
Kazuteru
K
Ikebe
Dai
D
Muto
Akihiko
A
Sun
Jiying
J
Kobayashi
Masao
M
Ueda
Kazuhiro
K
Melo
Junia V
JV
Igarashi
Kazuhiko
K
Tashiro
Satoshi
S
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000032:analysis*; D006570:Heterochromatin; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism; D008298:Maleates / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology / Q000633:toxicity; D011743:Pyrimidines / Q000494:pharmacology / Q000633:toxicity; D013997:Time Factors; D014158:Transcription, Genetic; D020298:U937 Cells
D000970:Antineoplastic Agents; C491123:BACH2 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D001549:Benzamides; D006570:Heterochromatin; D008298:Maleates; D010879:Piperazines; D011743:Pyrimidines; C406060:abl-bcr fusion protein, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C014476:diethyl maleate