TY - JOUR
T1 - Bifurcated BACH2 control coordinates mantle cell lymphoma survival and dispersal during hypoxia
AU - Zhang, Han
AU - Chen, Zheng
AU - Miranda, Roberto N.
AU - Medeiros, L. Jeffrey
AU - McCarty, Nami
N1 - Funding Information:
The authors thank Sanat Dave and the Anderson Hematopathology Tissue Bank for providing clinical samples for this study. This work was supported by grants from the American Cancer Society (Scholar Award RSG-11-157) and the National Institutes of Health, National Cancer Institute (grant R01CA181319) (N.M.).
Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/8/10
Y1 - 2017/8/10
N2 - BACH2, a B-cell–specific transcription factor, plays a critical role in oxidative stress–mediated drug resistance in mantle cell lymphoma (MCL); however, the biological functions of BACH2 and its regulation of B-cell malignancies in chronic hypoxic microenvironment have not been studied. Here, we found that silencing BACH2 led to not only increased tumor formation and colony formation but also increased tumor dispersal to spleen and bone marrow. Decreased BACH2 levels in patients were also correlated with bone marrow and gastrointestinal dispersal of MCL and blastoid subtypes of MCL. Unexpectedly, decreased BACH2 levels in dispersed MCL cells were due to direct transcriptional repression by hypoxia-induced factor 1a (HIF-1a) and increased heme-mediated protein degradation. In normoxic conditions, BACH2 was able to modulate HIF-1a degradation by suppressing prolyl hydroxylase 3 expression. Bifurcated BACH2 controls during hypoxia and normoxia coordinate not only MCL tumor dispersal but also drug resistance, including bortezomib resistance, via plasmacytic differentiation. Our data highlight an interactive relationship between tumor cells and local microenvironment and the mechanisms of B-cell transcription factor in the regulation of MCL dispersal.
AB - BACH2, a B-cell–specific transcription factor, plays a critical role in oxidative stress–mediated drug resistance in mantle cell lymphoma (MCL); however, the biological functions of BACH2 and its regulation of B-cell malignancies in chronic hypoxic microenvironment have not been studied. Here, we found that silencing BACH2 led to not only increased tumor formation and colony formation but also increased tumor dispersal to spleen and bone marrow. Decreased BACH2 levels in patients were also correlated with bone marrow and gastrointestinal dispersal of MCL and blastoid subtypes of MCL. Unexpectedly, decreased BACH2 levels in dispersed MCL cells were due to direct transcriptional repression by hypoxia-induced factor 1a (HIF-1a) and increased heme-mediated protein degradation. In normoxic conditions, BACH2 was able to modulate HIF-1a degradation by suppressing prolyl hydroxylase 3 expression. Bifurcated BACH2 controls during hypoxia and normoxia coordinate not only MCL tumor dispersal but also drug resistance, including bortezomib resistance, via plasmacytic differentiation. Our data highlight an interactive relationship between tumor cells and local microenvironment and the mechanisms of B-cell transcription factor in the regulation of MCL dispersal.
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U2 - 10.1182/blood-2017-02-767293
DO - 10.1182/blood-2017-02-767293
M3 - Article
C2 - 28592433
AN - SCOPUS:85028048335
SN - 0006-4971
VL - 130
SP - 763
EP - 776
JO - Blood
JF - Blood
IS - 6
ER -