Overexpression of MN1 confers resistance to chemotherapy, accelerates leukemia onset, and suppresses p53 and Bim induction.
BACKGROUND
The transcriptional co-activator MN1 confers a worse prognosis for patients with acute myeloid leukemia (AML) when highly expressed; however, the mechanisms involved are unknown. We sought to model the effects of high MN1 expression in AML models to explore the underlying mechanisms.


RESULTS
We used cell lines and a genetically defined mouse model of AML to examine the effects of MN1 overexpression on prognosis and response to cytarabine and doxorubicin in vitro and in vivo. Murine AML that was engineered to overexpress MN1 became more aggressive in vivo, leading to shortened survival in both treated and control groups. In vitro murine AML cells that overexpressed MN1 became resistant to treatment with cytarabine and highly resistant to doxorubicin. This resistant phenotype was also seen in vivo, where treatment with the combination of cytarabine and doxorubicin selected for cells expressing MN1. When therapy-induced DNA damage levels were assessed by γH2AX foci, no reduction was seen in MN1 expressing cells arguing against a drug efflux mechanism. Despite no reduction in DNA damage, MN1-expressing cells showed less apoptosis as assessed by annexin V and propidium iodide staining. Following treatment, p53 and BIM induction were markedly reduced in cells expressing MN1. Pharmacologic inhibition of the p53 E3 ligase MDM2 resulted in increased p53 levels and improved response to doxorubicin in vitro.


CONCLUSIONS
MN1 overexpression accelerates an already aggressive leukemia, confers resistance to chemotherapy, and suppresses p53 and BIM induction, resulting in decreased apoptosis. This provides a mechanistic explanation of the poor prognosis observed with high MN1 expression and suggests that therapies directed at increasing p53 function may be useful for these patients.
Wake Forest University Health Sciences, Department of Internal Medicine, Section on Hematology and Oncology, Winston-Salem, North Carolina, United States of America. tspardee@wakehealth.edu
Timothy S
TS
Pardee
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic; D006657:Histones / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D015513:Oncogene Proteins / Q000096:biosynthesis*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D006657:Histones; C506524:MN1 protein, human; D008565:Membrane Proteins; C501081:Mn1 protein, mouse; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003561:Cytarabine; D004317:Doxorubicin; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2