Mutations of the HIPK2 gene in acute myeloid leukemia and myelodysplastic syndrome impair AML1- and p53-mediated transcription.
The AML1 transcription factor complex is the most frequent target of leukemia-associated chromosomal translocations. Homeodomain-interacting protein kinase 2 (HIPK2) is a part of the AML1 complex and activates AML1-mediated transcription. However, chromosomal translocations and mutations of HIPK2 have not been reported. In the current study, we screened mutations of the HIPK2 gene in 50 cases of acute myeloid leukemia (AML) and in 80 cases of myelodysplastic syndrome (MDS). Results indicated there were two missense mutations (R868W and N958I) in the speckle-retention signal (SRS) domain of HIPK2. Subcellular localization analyses indicated that the two mutants were largely localized to nuclear regions with conical or ring shapes, and were somewhat diffused in the nucleus, in contrast to the wild type, which were mainly localized in nuclear speckles. The mutations impaired the overlapping localization of AML1 and HIPK2. The mutants showed decreased activities and a dominant-negative function over wild-type protein in AML1- and p53-dependent transcription. These findings suggest that dysfunction of HIPK2 may play a role in the pathogenesis of leukemia.
Li
X-L
XL
Molecular Oncology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Arai
Y
Y
Harada
H
H
Shima
Y
Y
Yoshida
H
H
Rokudai
S
S
Aikawa
Y
Y
Kimura
A
A
Kitabayashi
I
I
D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology*; D017931:DNA Primers; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D020125:Mutation, Missense; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D013347:Subcellular Fractions / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D002352:Carrier Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D017931:DNA Primers; C493728:RUNX1 protein, human; D016159:Tumor Suppressor Protein p53; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases