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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.

MDM4 Overexpressed in Acute Myeloid Leukemia Patients with Complex Karyotype and Wild-Type TP53