Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBPα (CCAAT/enhancer binding protein α) is frequently lost in non-small cell lung cancer, but the mechanisms by which C/EBPα suppresses tumor formation are not fully understood. In addition, no pharmacological therapy is available to specifically target C/EBPα expression. We discovered a subset of pulmonary adenocarcinoma patients in whom negative/low C/EBPα expression and positive expression of the oncogenic protein BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) have prognostic value. We also generated a lung-specific mouse model of C/EBPα deletion that develops lung adenocarcinomas, which are prevented by Bmi1 haploinsufficiency. BMI1 activity is required for both tumor initiation and maintenance in the C/EBPα-null background, and pharmacological inhibition of BMI1 exhibits antitumor effects in both murine and human adenocarcinoma lines. Overall, we show that C/EBPα is a tumor suppressor in lung cancer and that BMI1 is required for the oncogenic process downstream of C/EBPα loss. Therefore, anti-BMI1 pharmacological inhibition may offer a therapeutic benefit for lung cancer patients with low expression of C/EBPα and high BMI1.

Beth Israel Deaconess Medical Center Boston MA 02215 USA Harvard Medical School Boston MA 02215 USA

Beth Israel Deaconess Medical Center Boston MA 02215 USA Harvard Medical School Boston MA 02215 USA Harvard Stem Cell Institute Boston MA 02215 USA

Beth Israel Deaconess Medical Center Boston MA 02215 USA Harvard Medical School Boston MA 02215 USA Harvard Stem Cell Institute Boston MA 02215 USA Division of Hematology and Oncology Department of Medicine University of Alabama at Birmingham Birmingham AL 35233 USA

Beth Israel Deaconess Medical Center Boston MA 02215 USA Harvard Medical School Boston MA 02215 USA Harvard Stem Cell Institute Boston MA 02215 USA Hematology Division Department of Internal Medicine Ribeirao Preto Medical School University of São Paulo São Paulo 14020 Brazil

Beth Israel Deaconess Medical Center Boston MA 02215 USA Harvard Medical School Boston MA 02215 USA Harvard Stem Cell Institute Boston MA 02215 USA Institute of Biomedical Technologies National Research Council Pisa 56124 Italy

Beth Israel Deaconess Medical Center Boston MA 02215 USA Harvard Medical School Boston MA 02215 USA Harvard Stem Cell Institute Boston MA 02215 USA Institute of Molecular Genetics of the ASCR Prague 14200 Czech Republic

Beth Israel Deaconess Medical Center Boston MA 02215 USA Harvard Medical School Boston MA 02215 USA Stem Cell and Developmental Biology Genome Institute of Singapore Singapore 138672 Singapore

Biochemistry Department Chemistry Institute University of São Paulo São Paulo 05508 Brazil Beth Israel Deaconess Medical Center Boston MA 02215 USA Harvard Medical School Boston MA 02215 USA Harvard Stem Cell Institute Boston MA 02215 USA

Cancer Science Institute National University of Singapore Singapore 117599 Singapore

Cancer Science Institute National University of Singapore Singapore 117599 Singapore Department of Haematology Oncology University of Western Australia Crawley Western Australia 6009 Australia

Cancer Science Institute National University of Singapore Singapore 117599 Singapore Harvard Medical School Boston MA 02215 USA Harvard Stem Cell Institute Boston MA 02215 USA

Department of Biostatistics and Computational Biology Dana Farber Cancer Institute Boston MA 02215 USA

Department of Cellular and Molecular Medicine Graduate School of Medicine Chiba University Chiba 260 8670 Japan

Department of Pathology and Laboratory Medicine KK Women's and Children's Hospital Singapore 119074 Singapore

Department of Pathology Weill Cornell University Medical Center New York NY 10065 USA

Division of Hematology Oncology Montefiore Hospital Bronx NY 10461 USA

Institute of Biomedical Technologies National Research Council Pisa 56124 Italy

Laboratory of Receptor Biology and Gene Expression National Cancer Institute National Institutes of Health Bethesda MD 20817 USA

PTC Therapeutics 100 Corporate Court South Plainfield NJ 07080 USA

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