title: MDM4 overexpressed in acute myeloid leukemia patients with complex karyotype and wild-type TP53.
abstract: Acute myeloid leukemia patients with complex karyotype (CK-AML) account for approximately 10-15% of adult AML cases, and are often associated with a poor prognosis. Except for about 70% of CK-AML patients with biallelic inactivation of TP53, the leukemogenic mechanism in the nearly 30% of CK-AML patients with wild-type TP53 has remained elusive. In this study, 15 cases with complex karyotype and wild-type TP53 were screened out of 140 de novo AML patients and the expression levels of MDM4, a main negative regulator of p53-signaling pathway, were detected. We ruled out mutations in genes associated with a poor prognosis of CK-AML, including RUNX1 or FLT3-ITD. The mRNA expression levels of the full-length of MDM4 (MDM4FL) and short isoform MDM4 (MDM4S) were elevated in CK-AML relative to normal karyotype AML (NK-AML) patients. We also explored the impact of MDM4 overexpression on the cell cycle, cell proliferation and the spindle checkpoint of HepG2 cells, which is a human cancer cell line with normal MDM4 and TP53 expression. The mitotic index and the expression of p21, BubR1 and Securin were all reduced following Nocodazole treatment. Moreover, karyotype analysis showed that MDM4 overexpression might lead to aneuploidy or polyploidy. These results suggest that MDM4 overexpression is related to CK-AML with wild-type TP53 and might play a pathogenic role by inhibiting p53-signal pathway.
authors.affiliation: Department of Hematology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, P.R. China; Department of biology, School of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Hematology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, P.R. China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Hematology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, P.R. China.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Hematology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, P.R. China.
authors.forename: Zhifang
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Hematology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, P.R. China.
authors.forename: Siyao
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Hematology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, P.R. China.
authors.forename: Fanggang
authors.initials: F
authors.lastname: Ren
authors.affiliation: Department of biology, School of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi, P.R. China.
authors.forename: Haixiu
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Hematology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, P.R. China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Hematology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Hematology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, P.R. China.
authors.forename: Guoxia
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Hematology, the Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, P.R. China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
mesh_terms: D059786:Abnormal Karyotype; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D059566:M Phase Cell Cycle Checkpoints / Q000502:physiology; D015739:Nocodazole; D009687:Nuclear Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D017931:DNA Primers; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D015739:Nocodazole