PMID- 12032336
OWN - NLM
STAT- MEDLINE
DCOM- 20020701
LR  - 20220408
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 99
IP  - 11
DP  - 2002 May 28
TI  - 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.
PG  - 7640-5
AB  - 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.
FAU - Gu, Bai-Wei
AU  - Gu BW
AD  - 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.
FAU - Xiong, Hui
AU  - Xiong H
FAU - Zhou, Yan
AU  - Zhou Y
FAU - Chen, Bing
AU  - Chen B
FAU - Wang, Li
AU  - Wang L
FAU - Dong, Shuo
AU  - Dong S
FAU - Yu, Zhi-Yuan
AU  - Yu ZY
FAU - Lu, Ling-Feng
AU  - Lu LF
FAU - Zhong, Ming
AU  - Zhong M
FAU - Yin, Hai-Feng
AU  - Yin HF
FAU - Zhu, Gen-Feng
AU  - Zhu GF
FAU - Huang, Wei
AU  - Huang W
FAU - Ren, Shuang-Xi
AU  - Ren SX
FAU - Gallagher, Robert E
AU  - Gallagher RE
FAU - Waxman, Samuel
AU  - Waxman S
FAU - Chen, Guo-Qiang
AU  - Chen GQ
FAU - Wang, Zhu-Gang
AU  - Wang ZG
FAU - Chen, Zhu
AU  - Chen Z
FAU - Fu, Gang
AU  - Fu G
FAU - Chen, Sai-Juan
AU  - Chen SJ
LA  - eng
SI  - GENBANK/AC090426
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Oncogene Proteins, Fusion)
RN  - 0 (RARA protein, human)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoic Acid Receptor alpha)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Transcription Factors)
RN  - 0 (promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein)
RN  - 5688UTC01R (Tretinoin)
SB  - IM
MH  - Antineoplastic Agents/*therapeutic use
MH  - Base Sequence
MH  - Drug Resistance, Neoplasm/*genetics
MH  - *Genetic Variation
MH  - Humans
MH  - Introns
MH  - Leukemia, Promyelocytic, Acute/classification/drug therapy/*genetics
MH  - Molecular Sequence Data
MH  - Neoplasm Proteins/*genetics
MH  - Oncogene Proteins, Fusion/*genetics
MH  - Receptors, Retinoic Acid/*genetics
MH  - Retinoic Acid Receptor alpha
MH  - Retinoid X Receptors
MH  - Sequence Alignment
MH  - Sequence Analysis, DNA
MH  - Sequence Homology, Nucleic Acid
MH  - Transcription Factors/genetics
MH  - *Transcription, Genetic
MH  - Tretinoin/*therapeutic use
PMC - PMC124308
EDAT- 2002/05/29 10:00
MHDA- 2002/07/02 10:01
PMCR- 2002/11/28
CRDT- 2002/05/29 10:00
PHST- 2002/05/29 10:00 [pubmed]
PHST- 2002/07/02 10:01 [medline]
PHST- 2002/05/29 10:00 [entrez]
PHST- 2002/11/28 00:00 [pmc-release]
AID - 112194799 [pii]
AID - 1947 [pii]
AID - 10.1073/pnas.112194799 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2002 May 28;99(11):7640-5. doi: 10.1073/pnas.112194799.