Overexpression of BP1, a homeobox gene, is associated with resistance to all-trans retinoic acid in acute promyelocytic leukemia cells.
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.
Awwad
Rania T
RT
Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Ross Building, Room 533, 2300 Eye Street, NW, Washington, DC, 20037, USA.
Do
Khanh
K
Stevenson
Holly
H
Fu
Sidney W
SW
Lo-Coco
Francesco
F
Costello
Maura
M
Campbell
Cassandra L
CL
Berg
Patricia E
PE
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; C105304:DLX4 protein, human; D018398:Homeodomain Proteins; C489427:MYC protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D014212:Tretinoin