MDM4 overexpressed in acute myeloid leukemia patients with complex karyotype and wild-type TP53

PLoS One. 2014 Nov 18;9(11):e113088. doi: 10.1371/journal.pone.0113088. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormal Karyotype*
  • Blotting, Western
  • Cell Cycle Proteins
  • Cell Proliferation / physiology
  • DNA Primers / genetics
  • Gene Expression Regulation / physiology*
  • Hep G2 Cells
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism*
  • M Phase Cell Cycle Checkpoints / physiology
  • Nocodazole
  • Nuclear Proteins / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Statistics, Nonparametric
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Cell Cycle Proteins
  • DNA Primers
  • MDM4 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Nocodazole

Grant support

This study was supported by Natural Science Fund (81241014) of China, Natural Science Fund (2014011039-2) of Shanxi Province, University of Shanxi Science and Technology Development Project (20121004), Shanxi Medical Innovation Fund (C01201006), and Foundation for phD scientific research of Shanxi Medical University (03201309). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.