Società Italiana di Biofisica e Biologia Molecolare

 

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Premio Chiara D’Onofrio “Giovani” • 2018

Matteo_Pallocca

Matteo Pallocca

Abstract
Che-1/AATF-induced transcriptionally active chromatin promotes cell growth in Multiple Myeloma

Tumor transformation is the result of genetic modifications that alter gene transcription, resulting in a specific oncogenic program. In recent years, several exciting discoveries have shown that aberrant epigenetic modifications play a major role in the genesis and progression of cancer. Multiple myeloma (MM) is a cancerous pathology resulting from a clonal expansion of plasma cells, characterized by abnormal production and secretion of monoclonal antibody proteins. This disease shows a great heterogeneity, caused not only by genetic abnormalities but also by numerous epigenetic aberrations. Here we demonstrate that the RNA Polymerase II (Pol II) binding protein, Che-1 is required for MM cell growth by sustaining genome wide transcription and recruitment of Pol II to the DNA. Notably, we found that Che-1 localizes on active chromatin and that its depletion leads to accumulation of heterochromatin by a global decrease of histone acetylation. Strikingly, transgenic mice expressing human Che-1 in plasma cells develop MM with clinical features resembling those observed in the human disease. Moreover, Che-1 downregulation decreases BRD4 chromatin accumulation to further sensitize MM cells to bromodomain and extra-terminal (BET) inhibitors. In summary, our findings identify Che-1 as a key player for maintaining open chromatin required for sustaining MM growth. These findings support Che-1 as a possible target for MM therapy, alone or in combination with BET inhibitors.