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Tumor transformation is the result of genetic and epigenetic modifications that alter gene transcription, consequently producing a specific oncogenic program. Multiple myeloma (MM) is a neoplasia characterized by the accumulation of proliferating antibodies producing plasma cells in the bone marrow. This disease is the second most frequent haematological malignancy in the US and Europe. In this study we demonstrate that Che-1 plays a crucial role in the control of transcription and cellular proliferation by regulating the state of the chromatin and by increasing its accessibility, highlighting Che-1 as an essential component of the transcription machinery in MM. Che-1 loss induces a global transcription shut-off, by reducing RNA Pol II recruitment onto the DNA. Most importantly, transcriptional inhibition in Che-1 depleted cells could already be detected at pre-mRNA levels, leading to the hypothesis that Che-1 could regulate RNA pol II activity directly. Our study shows that Che-1 is required for the maintenance of open chromatin in MM cells, and is involved in general histone acetylation. Morever, we found that Che-1 downregulation further sensitizes MM cells to bromodomain and extra-terminal (BET) inhibitors. Indeed Che-1 silencing increased JQ1 sensitivity of MM cells. In summary, our findings identify Che-1 as a key player for maintaining the open chromatin structure required for sustaining MM growth. These findings support Che-1 as a possible target for MM therapy, alone or in combination with BET inhibitors. Citation Format: Tiziana Bruno, Francesca De Nicola, Frauke Goeman, Matteo Pallocca, Cristina Sorino, Valeria Catena, Gianluca Bossi, Bruno Amadio, Giovanni Cigliana, Enrico Spugnini, Maria Rosaria Ricciardi, Maria Teresa Petrucci, Alfonso Baldi, Mario Cioce, Giancarlo Cortese, Elisabetta Mattei, Roberta Merola, Umberto Gianelli, Francesco Pisani, Svitlana Gumenyuk, Andrea Mengarelli, Katja Hopker, Thomas Benzing, Aristide Floridi, Claudio Passananti, Giovanni Blandino, Simona Iezzi, Maurizio Fanciulli. Che-1/aatf-induced transcriptionally active chromatin promotes cell growth in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 350.

Clinical management of Malignant Pleural Mesothelioma (MPM) is very challenging because of the uncommon resistance of the tumor to chemotherapy. We started from the observation that 7/7 mesothelioma cell lines tested expressed both the Colony Stimulating Factor Receptor-1 and its -ligands CSF-1 and IL-34, a signaling module mainly characterized in hematopoietic cell subpopulations. Pemetrexed and cisplatin treatment did not affect the number of mesothelioma CSF1R-expressing cells. Additionally, interference with CSF1R expression or function significantly abrogated the resistance of these cells to pemetrexed, suggesting the involvement of CSF-1R signaling in mediating chemoresistance of mesothelioma. This prompted us to isolate and characterize the CSF-1Rpos cells and we found that the purified cells expressed a complex repertoire of pluripotency markers, EMT factors and chemoresistance genes. The functions of the CSF-1R expressing MPM cells relied on the autocrine production of CSF-1 and IL-34, whose downregulation affected the viability of the purified cells. We identified AKT, NFkB and STAT3 activation as distinct features of the CSF-1Rpos cells. We showed that all three pathways contributed to the survival of the CSF1Rpos cells, with AKT exerting the most relevant effects. The forced activation of CSF-1R in untransformed mesothelial cells was sufficient to confer clonogenicity and resistance to pemetrexed, typical feature of transformed mesothelial cells. Furthermore, this induced a gene expression profile very similar to that observed in the FACS sorted CSF-1Rpos cells, suggesting a causal relationship between CSF-1R activation and cell transformation. Active AKT signaling contributed to increased levels of nuclear β-catenin in the CSF-1R expressing cells. Inhibition of AKT reduced the transcriptional activity of β-catenin dependent reporters and sensitized the CSF-1Rpos cells to pemetrexed-induced senescence, thereby reversing the resistance of the CSF1Rpos cells to pemetrexed. This correlated with downregulation of c-MYC, a functional CSF-1R target, and upregulation of p21. Finally, we recapitulated the main findings in primary mesothelioma cultures, which exhibited long-term surviving, chemoresistant CSF-1Rpos cells of mesothelial nature and sensitive to CSF-1R inhibition. This work expands what is known on the non-macrophage functions of CSF-1R and its role in solid tumors, suggests that CSF-1R signaling may have a critical pathogenic role in malignant pleural mesothelioma and therefore may represent a promising target for therapeutic intervention. Citation Format: Mario Cioce, Claudia Canino, Chandra Goparaju, Haining Yang, Michele Carbone, Harvey I. Pass. CSF-1R signaling drives mesothelioma stemness and chemoresistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4404. doi:10.1158/1538-7445.AM2014-4404