Disease-related potential of mutations in transcriptional cofactors CREB-binding protein and p300 in leukemias.
CREB-binding protein (CBP) and highly related p300 protein are transcriptional co-activators that play an essential role in chromatin remodeling through histone acetyltransferase activity and interaction with other transcriptional regulators. In this study, various hematological malignancies, including nine cell lines and 45 clinical samples (32 acute myeloid leukemias (AML), nine acute lymphoblastic leukemias (ALL), two cases of myelodysplastic syndrome (MDS), one multiple myeloma, and one chronic myelogenous leukemia in blast crisis), were examined to ask whether mutation of the CBP and p300 genes could be involved in leukemogenesis. The answer was approached by employing the reverse transcription-polymerase chain reaction and single-strand conformation polymorphism (RT-PCR/SSCP) technique and subsequent sequence analysis. A T-lymphoblastic cell line, CEM had an in-frame 21-base-pair deletion within the bromodomain of its p300 cDNA. Genomic DNA analysis revealed aberrant splicing caused by mutation of the acceptor site of intron 17 from ag to gg, which should interfere with catalytic step II of the pre-mRNA splicing reaction. In 1 MDS patient, a missense mutation was detected, which caused a replacement from Ser to Gly at codon 507 of p300. This is the first report of CBP/p300 mutations in leukemias, which might be relatively rare but nonetheless contribute to pathogenesis in some fraction of cases.
Shigeno
Kazuyuki
K
Department of Medicine III, Hamamatsu University School of Medicine, Japan.
Yoshida
Hitoshi
H
Pan
Ling
L
Luo
Jian Min
JM
Fujisawa
Shinya
S
Naito
Kensuke
K
Nakamura
Satoki
S
Shinjo
Kaori
K
Takeshita
Akihiro
A
Ohno
Ryuzo
R
Ohnishi
Kazunori
K
D000123:Acetyltransferases; D050882:CREB-Binding Protein; D004252:DNA Mutational Analysis; D017931:DNA Primers; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000503:physiopathology*; D009101:Multiple Myeloma / Q000235:genetics* / Q000503:physiopathology*; D020125:Mutation, Missense; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics*; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D009687:Nuclear Proteins; D015534:Trans-Activators; D000123:Acetyltransferases; D050882:CREB-Binding Protein; C494363:CREBBP protein, human