A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein.
Acute promyelocytic leukemia (APL) is associated with a t(15;17) translocation that creates the promyelocyte-retinoic acid receptor alpha (PML-RAR alpha) fusion gene. Immunohistochemistry demonstrates that PML is a part of a novel macromolecular organelle (including at least three other nuclear proteins) referred to as PML oncogenic domains (PODs). In APL cells, the POD is disrupted into a microparticulate pattern as a consequence of the expression of the PML-RAR oncoprotein. RA treatment of APL cells triggers a reorganization of PML to generate normal-appearing PODs. We propose that PML-RAR is a dominant negative oncoprotein that exerts its putative leukomogenic effect by inhibiting assembly of the POD. According to this proposal, not only is the POD a novel structure, but it can be ascribed an imputed function such that its disruption leads to altered myeloid maturation; this may represent a novel oncogenic target.
Dyck
J A
JA
Biomedical Sciences Graduate Progam University of California, San Diego, La Jolla 92037.
Maul
G G
GG
Miller
W H
WH
Chen
J D
JD
Kakizuka
A
A
Evans
R M
RM
D002467:Cell Nucleus / Q000648:ultrastructure*; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D005455:Fluorescent Antibody Technique; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D009857:Oncogenes; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism*; D014178:Translocation, Genetic; D014212:Tretinoin / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D014212:Tretinoin