title: Variant-type PML-RAR(alpha) fusion transcript in acute promyelocytic leukemia: use of a cryptic coding sequence from intron 2 of the RAR(alpha) gene and identification of a new clinical subtype resistant to retinoic acid therapy.
abstract: The physiologic actions of retinoic acids (RAs) are mediated through RA receptors (RARs) and retinoid X receptors (RXRs). The RAR(alpha) gene has drawn particular attention because it is the common target in all chromosomal translocations in acute promyelocytic leukemia (APL), a unique model in cancer research that responds to the effect of RA. In the great majority of patients with APL, RAR(alpha) is fused to the PML gene as a result of the t(15;17) translocation. Three distinct types of PML-RAR(alpha) transcripts, long (L), short (S), and variant (V), were identified. The V-type is characterized by truncation of exon 6 of PML and in some cases by the insertion of a variable "spacer" sequence between the truncated PML and RAR(alpha) mRNA fusion partners, although the precise mechanisms underlying formation of the V-type transcript remain unclear. To get further insights into the molecular basis of the t(15;17), we sequenced the entire genomic DNA region of RAR(alpha). Of note, all previously reported "spacer" sequences in V-type transcripts were found in intron 2 of the RAR(alpha) gene and most of these sequences were flanked by gt splice donor sites. In most cases, these "cryptic" coding sequences maintained the ORF of the chimeric transcript. Interestingly, two cases with a relatively long spacer sequence showed APL cellular and clinical resistance to RA treatment. In these cases, the aberrant V-type PML-RAR(alpha) protein displayed increased affinity to the nuclear corepressor protein SMRT, providing further evidence that RA exerts the therapeutic effect on APL through modulation of the RAR-corepressor interaction. Finally, among patients with the L- or S-type PML-RAR(alpha) fusion transcript, some consensus motifs were identified at the hotspots of the chromosome 17q breakpoints within intron 2 of RAR(alpha), strengthening the importance of this intron in the molecular pathogenesis of APL.
authors.affiliation: State Key Lab for Medical Genomics and Samuel Waxman Cancer Research Foundation Lab, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Second Medical University, 197 Rui Jin Road II, Shanghai 200025, China.
authors.forename: Bai-Wei
authors.initials: BW
authors.lastname: Gu
authors.forename: Hui
authors.initials: H
authors.lastname: Xiong
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Shuo
authors.initials: S
authors.lastname: Dong
authors.forename: Zhi-Yuan
authors.initials: ZY
authors.lastname: Yu
authors.forename: Ling-Feng
authors.initials: LF
authors.lastname: Lu
authors.forename: Ming
authors.initials: M
authors.lastname: Zhong
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Yin
authors.forename: Gen-Feng
authors.initials: GF
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Shuang-Xi
authors.initials: SX
authors.lastname: Ren
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gallagher
authors.forename: Samuel
authors.initials: S
authors.lastname: Waxman
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Chen
authors.forename: Zhu-Gang
authors.initials: ZG
authors.lastname: Wang
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Gang
authors.initials: G
authors.lastname: Fu
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001483:Base Sequence; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D007438:Introns; D015473:Leukemia, Promyelocytic, Acute / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D014212:Tretinoin / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014157:Transcription Factors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin