Activation of Notch and Myc signaling via B cell-restricted depletion of Dnmt3a generates a consistent murine model of chronic lymphocytic leukemia
| Autor: | Laura Z. Rassenti, Elisa Ten Hacken, Arman W. Mohammad, Eugen Tausch, Lili Wang, Mohamed Uduman, Jennifer R. Brown, Ruben D. Carrasco, Andreas Gnirke, Stacey M. Fernandes, Shanye Yin, Elizabeth Witten, Clare Sun, Catherine J. Wu, Alexander Meissner, Nathan J Dangle, Catherine Gutierrez, Fara Faye Regis, Gabriela Brunsting Hoffmann, Fabienne Lucas, Thomas J. Kipps, Kristen E. Stevenson, Donna Neuberg, Anthony Letai, Jon C. Aster, Anat Biran, Stephan Stilgenbauer, Salma Parvin, Mei Zheng, Helene Kretzmer, Leah Billington |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Cancer Research Methyltransferase Lymphoma Somatic cell Chronic lymphocytic leukemia Drug Resistance Apoptosis Mice SCID DNA Methyltransferase 3A Mice immune system diseases Mice Inbred NOD hemic and lymphatic diseases Conditional gene knockout Receptors Tumor Cells Cultured 2.1 Biological and endogenous factors RNA-Seq Chronic Aetiology Cancer Mice Knockout Cultured Leukemia Tumor Receptors Notch Hematology Prognosis Lymphocytic Tumor Cells Anti-Bacterial Agents Gene Expression Regulation Neoplastic Survival Rate medicine.anatomical_structure Oncology DNA methylation embryonic structures Female Notch Knockout Oncology and Carcinogenesis Notch signaling pathway Biology SCID Article Proto-Oncogene Proteins c-myc Rare Diseases Daptomycin medicine Genetics Biomarkers Tumor Animals Humans Epigenetics Oncology & Carcinogenesis B cell Cell Proliferation Neoplastic Animal B-Cell medicine.disease Leukemia Lymphocytic Chronic B-Cell Xenograft Model Antitumor Assays Disease Models Animal Gene Expression Regulation Drug Resistance Neoplasm Disease Models Cancer research Inbred NOD Neoplasm Biomarkers |
| Zdroj: | Cancer Res Cancer research, vol 81, iss 24 |
| Popis: | Chronic lymphocytic leukemia (CLL) is characterized by disordered DNA methylation, suggesting these epigenetic changes might play a critical role in disease onset and progression. The methyltransferase DNMT3A is a key regulator of DNA methylation. Although DNMT3A somatic mutations in CLL are rare, we found that low DNMT3A expression is associated with more aggressive disease. A conditional knockout mouse model showed that homozygous depletion of Dnmt3a from B cells results in the development of CLL with 100% penetrance at a median age of onset of 5.3 months, and heterozygous Dnmt3a depletion yields a disease penetrance of 89% with a median onset at 18.5 months, confirming its role as a haploinsufficient tumor suppressor. B1a cells were confirmed as the cell of origin of disease in this model, and Dnmt3a depletion resulted in focal hypomethylation and activation of Notch and Myc signaling. Amplification of chromosome 15 containing the Myc gene was detected in all CLL mice tested, and infiltration of high-Myc–expressing CLL cells in the spleen was observed. Notably, hyperactivation of Notch and Myc signaling was exclusively observed in the Dnmt3a CLL mice, but not in three other CLL mouse models tested (Sf3b1-Atm, Ikzf3, and MDR), and Dnmt3a-depleted CLL were sensitive to pharmacologic inhibition of Notch signaling in vitro and in vivo. Consistent with these findings, human CLL samples with lower DNMT3A expression were more sensitive to Notch inhibition than those with higher DNMT3A expression. Altogether, these results suggest that Dnmt3a depletion induces CLL that is highly dependent on activation of Notch and Myc signaling. Significance: Loss of DNMT3A expression is a driving event in CLL and is associated with aggressive disease, activation of Notch and Myc signaling, and enhanced sensitivity to Notch inhibition. |
| Databáze: | OpenAIRE |
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