Overexpression of BP1, a homeobox gene,is associated with resistance to all-trans retinoic acid in acute promyelocytic leukemia cells |
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Authors: | Rania T Awwad Khanh Do Holly Stevenson Sidney W Fu Francesco Lo-Coco Maura Costello Cassandra L Campbell Patricia E Berg |
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Institution: | (1) Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Ross Building, Room 533, 2300 Eye Street, NW, Washington, DC 20037, USA;(2) The George Washington University School of Medicine, Washington, DC, USA;(3) Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;(4) Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Ross Building, Room 536, 2300 Eye Street, NW, Washington, DC 20037, USA;(5) Department of Biopathology, University Tor Vergata, Rome, Italy |
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Abstract: | BP1, a homeobox gene, is overexpressed in the bone marrow of 63% of acute myeloid leukemia patients. In this study, we compared
the growth-inhibitory and cyto-differentiating activities of all-trans retinoic acid (ATRA) in NB4 (ATRA-responsive) and R4
(ATRA-resistant) acute promyelocytic leukemia (APL) cells relative to BP1 levels. Expression of two oncogenes, bcl-2 and c-myc, was also assessed. NB4 and R4 cells express BP1, bcl-2, and c-myc; the expression of all three genes was repressed after ATRA treatment of NB4 cells but not R4 cells. To determine whether
BP1 overexpression affects sensitivity to ATRA, NB4 cells were transfected with a BP1-expressing plasmid and treated with
ATRA. In cells overexpressing BP1: (1) proliferation was no longer inhibited; (2) differentiation was reduced two- to threefold;
(3) c-myc was no longer repressed. These and other data suggest that BP1 may regulate bcl-2 and c-myc expression. Clinically, BP1 levels were elevated in all pretreatment APL patients tested, while BP1 expression was decreased
in 91% of patients after combined ATRA and chemotherapy treatment. Two patients underwent disease relapse during follow-up;
one patient exhibited a 42-fold increase in BP1 expression, while the other showed no change. This suggests that BP1 may be
part of a pathway involved in resistance to therapy. Taken together, our data suggest that BP1 is a potential therapeutic
target in APL.
Rania T. Awwad and Khanh Do contributed equally to the present study. |
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Keywords: | Acute promyelocytic leukemia All-trans retinoic acid Homeobox BP1 |
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