CDKN1A and FANCD2 are potential oncotargets in Burkitt lymphoma and multiple myeloma

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• 作者：Seong-Su Han ; Van S Tompkins ; Dong-Ju Son…
• 关键词：p21 tumor suppressor ; Fanconi anemia and breast cancer DNA damage repair ; Genetically engineered mouse models of human cancer ; Molecularly targeted cancer therapy
• 刊名：Experimental Hematology & Oncology
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：4
• 期：1
• 全文大小：1,979 KB
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• 刊物主题：Hematology; Oncology;
• 出版者：BioMed Central
• ISSN：2162-3619

文摘

Background Comparative genetic and biological studies on malignant tumor counterparts in human beings and laboratory mice may be powerful gene discovery tools for blood cancers, including neoplasms of mature B-lymphocytes and plasma cells such as Burkitt lymphoma (BL) and multiple myeloma (MM). Methods We used EMSA to detect constitutive NF-κB/STAT3 activity in BL- and MM-like neoplasms that spontaneously developed in single-transgenic IL6 (interleukin-6) or MYC (c-Myc) mice, or in double-transgenic IL6MYC mice. qPCR measurements and analysis of clinical BL and MM datasets were employed to validate candidate NF-κB/STAT3 target genes. Results qPCR demonstrated that IL6- and/or MYC-dependent neoplasms in mice invariably contain elevated mRNA levels of the NF-κB target genes, Cdkn1a and Fancd2. Clinical studies on human CDKN1A, which encodes the cell cycle inhibitor and tumor suppressor p21, revealed that high p21 message predicts poor therapy response and survival in BL patients. Similarly, up-regulation of FANCD2, which encodes a key member of the Fanconi anemia and breast cancer pathway of DNA repair, was associated with poor outcome of patients with MM, particularly those with high-risk disease. Conclusions Our findings suggest that CDKN1A and FANCD2 are potential oncotargets in BL and MM, respectively. Additionally, the IL-6- and/or MYC-driven mouse models of human BL and MM used in this study may lend themselves to the biological validation of CDKN1A and FANCD2 as molecular targets for new approaches to cancer therapy and prevention.