title: Global down-regulation of HOX gene expression in PML-RARalpha + acute promyelocytic leukemia identified by small-array real-time PCR.
abstract: Acute promyelocytic leukemia (APL) is associated with a reciprocal and balanced translocation involving the retinoic acid receptor-alpha (RARalpha). All-trans retinoic acid (ATRA) is used to treat APL and is a potent morphogen that regulates HOX gene expression in embryogenesis and organogenesis. HOX genes are also involved in hematopoiesis and leukemogenesis. Thirty-nine mammalian HOX genes have been identified and classified into 13 paralogous groups clustered on 4 chromosomes. They encode a complex network of transcription regulatory proteins whose precise targets remain poorly understood. The overall function of the network appears to be dictated by gene dosage. To investigate the mechanisms involved in HOX gene regulation in hematopoiesis and leukemogenesis by precise measurement of individual HOX genes, a small-array real-time HOX (SMART-HOX) quantitative polymerase chain reaction (PCR) platform was designed and validated. Application of SMART-HOX to 16 APL bone marrow samples revealed a global down-regulation of 26 HOX genes compared with normal controls. HOX gene expression was also altered during differentiation induced by ATRA in the PML-RARalpha(+) NB4 cell line. PML-RARalpha fusion proteins have been reported to act as part of a repressor complex during myeloid cell differentiation, and a model linking HOX gene expression to this PML-RARalpha repressor complex is now proposed.
authors.affiliation: Department of Haematology, Cancer Research Centre, Queen's University, Belfast, Northern Ireland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Thompson
authors.forename: Michael F
authors.initials: MF
authors.lastname: Quinn
authors.forename: David
authors.initials: D
authors.lastname: Grimwade
authors.forename: Claire M
authors.initials: CM
authors.lastname: O'Neill
authors.forename: Momin R
authors.initials: MR
authors.lastname: Ahmed
authors.forename: Sean
authors.initials: S
authors.lastname: Grimes
authors.forename: Mary Frances
authors.initials: MF
authors.lastname: McMullin
authors.forename: Finbarr
authors.initials: F
authors.lastname: Cotter
authors.forename: Terence R J
authors.initials: TR
authors.lastname: Lappin
mesh_terms: D001853:Bone Marrow / Q000737:chemistry; D002454:Cell Differentiation / Q000187:drug effects; D003001:Cloning, Molecular; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000032:analysis*; D015514:Oncogene Proteins, Fusion / Q000032:analysis*; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin