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

Li Li,Yi Chen,Yanhong Tan,Hongwei Wang,Haixiu Guo,Xiuhua Chen,Siyao Yang,Xiaojuan Wang,Guoxia Li,Zhifang Xu,Fanggang Ren,Ken Mills

doi:10.1371/journal.pone.0113088

Li Li, Yi Chen + Show 10 more

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https://doi.org/10.1371/journal.pone.0113088

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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.

Highlights

Acute myeloid leukemia patients with complex karyotype (CKAML) account for approximately 10–15% of adult AML, and the incidence increases with age
A series of large sample studies show that nearly 70% of CK-AML cases carry TP53 mutations and have biallelic inactivation of TP53 [4,5]. p53 plays an important role in spindle damage induced mitotic arrest in proliferating T cells [6] and p53 lost myeloid progenitors exhibit aberrant self-renewal, thereby promoting AML[7]
CK-AML patients with wild-type TP53 correlated with poorer prognosis than normal karyotype AML (NK-AML) patients This study cohort included 15 CK-AML patients with wild-type

Summary

Introduction

Acute myeloid leukemia patients with complex karyotype (CKAML) account for approximately 10–15% of adult AML, and the incidence increases with age. The molecular mechanisms mediating of leukemogenesis in CK-AML patients have remained elusive. A series of large sample studies show that nearly 70% of CK-AML cases carry TP53 mutations and have biallelic inactivation of TP53 [4,5]. The question remains as to the leukemogenic mechanisms of the nearly 30% of CK-AML patients without TP53 alterations. MDM4 is a negative regulator of p53, and by binding p53, close the transcriptional activity domain and thereby inhibits p53 function [8]. MDM4S is essentially a truncated protein that mainly consists of the p53binding domain. MDM4S has been reported to bind and inhibit p53 more efficiently than full-length MDM4 (MDM4FL) [9]

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