Person: Levantini, Elena
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Levantini
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Elena
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Levantini, Elena
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Publication C/EBPa controls acquisition and maintenance of adult hematopoietic stem cell quiescence(2013) Ye, Min; Zhang, Hong; Amabile, Giovanni; Yang, Henry; Staber, Philipp B.; Zhang, Pu; Levantini, Elena; Alberich-Jordà, Meritxell; Zhang, Junyan; Kawasaki, Akira; Tenen, DanielSummary In blood, transcription factor C/EBPa is essential for myeloid differentiation and has been implicated in regulating self-renewal of fetal liver (FL) hematopoietic stem cells (HSCs). However, its function in adult HSCs has remained unknown. Here, using an inducible knockout model we found that C/EBPa deficient adult HSCs underwent a pronounced expansion with enhanced proliferation, characteristics resembling FL HSCs. Consistently, transcription profiling of C/EBPa deficient HSCs revealed a gene expression programme similar to FL HSCs. Moreover we observed that age-specific C/EBPa expression correlated with its inhibitory effect on HSC cell cycle. Mechanistically we identified N-Myc as C/EBPa downstream target, and loss of C/EBPa resulted in de-repression of N-Myc. Our data establish C/EBPa as a central determinant in the switch from fetal to adult HSCs.Publication Aurora kinase targeting in lung cancer reduces KRAS-induced transformation(BioMed Central, 2016) dos Santos, Edmilson Ozorio; Carneiro-Lobo, Tatiana Correa; Aoki, Mateus Nobrega; Levantini, Elena; Bassères, Daniela SanchezBackground: Activating mutations in KRAS are prevalent in lung cancer and have been causally linked to the oncogenic process. However, therapies targeted to oncogenic RAS have been ineffective to date and identification of KRAS targets that impinge on the oncogenic phenotype is warranted. Based on published studies showing that mitotic kinases Aurora A (AURKA) and B (AURKB) cooperate with oncogenic RAS to promote malignant transformation and that AURKA phosphorylates RAS effector pathway components, the aim of this study was to investigate whether AURKA and AURKB are KRAS targets in lung cancer and whether targeting these kinases might be therapeutically beneficial. Methods: In order to determine whether oncogenic KRAS induces Aurora kinase expression, we used qPCR and western blotting in three different lung cell-based models of gain- or loss-of-function of KRAS. In order to determine the functional role of these kinases in KRAS-induced transformation, we generated KRAS-positive A549 and H358 cells with stable and inducible shRNA-mediated knockdown of AURKA or AURKB and evaluated transformation in vitro and tumor growth in vivo. In order to validate AURKA and/or AURKB as therapeutically relevant KRAS targets in lung cancer, we treated A549 and H358 cells, as well as two different lung cell based models of gain-of-function of KRAS with a dual Aurora kinase inhibitor and performed functional in vitro assays. Results: We determined that KRAS positively regulates AURKA and AURKB expression. Furthermore, in KRAS-positive H358 and A549 cell lines, inducible knockdown of AURKA or AURKB, as well as treatment with a dual AURKA/AURKB inhibitor, decreased growth, viability, proliferation, transformation, and induced apoptosis in vitro. In addition, inducible shRNA-mediated knockdown of AURKA in A549 cells decreased tumor growth in vivo. More importantly, dual pharmacological inhibiton of AURKA and AURKB reduced growth, viability, transformation, and induced apoptosis in vitro in an oncogenic KRAS-dependent manner, indicating that Aurora kinase inhibition therapy can specifically target KRAS-transformed cells. Conclusions: Our results support our hypothesis that Aurora kinases are important KRAS targets in lung cancer and suggest Aurora kinase inhibition as a novel approach for KRAS-induced lung cancer therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12943-016-0494-6) contains supplementary material, which is available to authorized users.Publication Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia(American Society of Hematology, 2009) Guibal, F. C.; Alberich-Jorda, M.; Hirai, H.; Ebralidze, Alexander; Levantini, Elena; Di Ruscio, A.; Zhang, Pu; Santana-Lemos, B. A.; Neuberg, Donna; Wagers, Amy; Rego, E. M.; Tenen, DanielAcute promyelocytic leukemia (APL) is characterized by a block in differentiation and accumulation of promyelocytes in the bone marrow and blood. The majority of APL patients harbor the t(15:17) translocation leading to expression of the fusion protein promyelocytic-retinoic acid receptor . Treatment with retinoic acid leads to degradation of promyelocyticretinoic acid receptor protein and disappearance of leukemic cells; however, 30% of APL patients relapse after treatment. One potential mechanism for relapse is the persistence of cancer “stem” cells in hematopoietic organs after treatment. Using a novel sorting strategy we developed to isolate murine myeloid cells at distinct stages of differentiation, we identified a population of committed myeloid cells (CD34, c-kit, FcRIII/II, Gr1int) that accumulates in the spleen and bone marrow in a murine model of APL. We observed that these cells are capable of efficiently generating leukemia in recipient mice, demonstrating that this population represents the APL cancer–initiating cell. These cells down-regulate the transcription factor CCAAT/enhancer binding protein (C/EBP) possibly through a methylationdependent mechanism, indicating that C/EBP deregulation contributes to transformation of APL cancer–initiating cells. Our findings provide further understanding of the biology of APL by demonstrating that a committed transformed progenitor can initiate and propagate the disease.Publication Dissecting the role of aberrant DNA methylation in human leukemia(2015) Amabile, Giovanni; Di Ruscio, Annalisa; Müller, Fabian; Welner, Robert S; Yang, Henry; Ebralidze, Alexander; Zhang, Hong; Levantini, Elena; Qi, Lihua; Martinelli, Giovanni; Brummelkamp, Thijn; Le Beau, Michelle M; Figueroa, Maria E; Bock, Christoph; Tenen, DanielChronic Myeloid Leukemia (CML) is a myeloproliferative disorder characterized by the genetic translocation t(9;22)(q34;q11.2) encoding for the BCR-ABL fusion oncogene. However, many molecular mechanisms of the disease progression still remain poorly understood. A growing body of evidence suggests that epigenetic abnormalities are involved in tyrosine kinase resistance in CML, leading to leukemic clone escape and disease propagation. Here we show that, by applying cellular reprogramming to primary CML cells, aberrant DNA methylation contributes to the disease evolution. Importantly, using a BCR-ABL inducible murine model, we demonstrate that a single oncogenic lesion triggers DNA methylation changes which in turn act as a precipitating event in leukemia progression.Publication CCAAT/Enhancer Binding Protein β Is Dispensable for Development of Lung Adenocarcinoma(Public Library of Science, 2015) Cai, Yi; Hirata, Ayako; Nakayama, Sohei; Vanderlaan, Paul; Levantini, Elena; Yamamoto, Mihoko; Hirai, Hideyo; Wong, Kwok-Kin; Costa, Daniel; Watanabe, Hideo; Kobayashi, SusumuLung cancer is the leading cause of cancer death worldwide. Although disruption of normal proliferation and differentiation is a vital component of tumorigenesis, the mechanisms of this process in lung cancer are still unclear. A transcription factor, C/EBPβ is a critical regulator of proliferation and/or differentiation in multiple tissues. In lung, C/EBPβ is expressed in alveolar pneumocytes and bronchial epithelial cells; however, its roles on normal lung homeostasis and lung cancer development have not been well described. Here we investigated whether C/EBPβ is required for normal lung development and whether its aberrant expression and/or activity contribute to lung tumorigenesis. We showed that C/EBPβ was expressed in both human normal pneumocytes and lung adenocarcinoma cell lines. We found that overall lung architecture was maintained in Cebpb knockout mice. Neither overexpression of nuclear C/EBPβ nor suppression of CEBPB expression had significant effects on cell proliferation. C/EBPβ expression and activity remained unchanged upon EGF stimulation. Furthermore, deletion of Cebpb had no impact on lung tumor burden in a lung specific, conditional mutant EGFR lung cancer mouse model. Analyses of data from The Cancer Genome Atlas (TCGA) revealed that expression, promoter methylation, or copy number of CEBPB was not significantly altered in human lung adenocarcinoma. Taken together, our data suggest that C/EBPβ is dispensable for development of lung adenocarcinoma.Publication Acetylation of C/EBPα inhibits its granulopoietic function(Nature Publishing Group, 2016) Bararia, Deepak; Kwok, Hui Si; Welner, Robert S.; Numata, Akihiko; Sárosi, Menyhárt B.; Yang, Henry; Wee, Sheena; Tschuri, Sebastian; Ray, Debleena; Weigert, Oliver; Levantini, Elena; Ebralidze, Alexander; Gunaratne, Jayantha; Tenen, DanielCCAAT/enhancer-binding protein alpha (C/EBPα) is an essential transcription factor for myeloid lineage commitment. Here we demonstrate that acetylation of C/EBPα at lysine residues K298 and K302, mediated at least in part by general control non-derepressible 5 (GCN5), impairs C/EBPα DNA-binding ability and modulates C/EBPα transcriptional activity. Acetylated C/EBPα is enriched in human myeloid leukaemia cell lines and acute myeloid leukaemia (AML) samples, and downregulated upon granulocyte-colony stimulating factor (G-CSF)- mediated granulocytic differentiation of 32Dcl3 cells. C/EBPα mutants that mimic acetylation failed to induce granulocytic differentiation in C/EBPα-dependent assays, in both cell lines and in primary hematopoietic cells. Our data uncover GCN5 as a negative regulator of C/EBPα and demonstrate the importance of C/EBPα acetylation in myeloid differentiation.Publication Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non‐small cell lung cancer(John Wiley and Sons Inc., 2018) Ali, Azhar; Levantini, Elena; Teo, Jun Ting; Goggi, Julian; Clohessy, John; Wu, Chan Shuo; Chen, Leilei; Yang, Henry; Krishnan, Indira; Kocher, Olivier; Zhang, Junyan; Soo, Ross A; Bhakoo, Kishore; Chin, Tan Min; Tenen, DanielAbstract Metabolic reprogramming is widely known as a hallmark of cancer cells to allow adaptation of cells to sustain survival signals. In this report, we describe a novel oncogenic signaling pathway exclusively acting in mutated epidermal growth factor receptor (EGFR) non‐small cell lung cancer (NSCLC) with acquired tyrosine kinase inhibitor (TKI) resistance. Mutated EGFR mediates TKI resistance through regulation of the fatty acid synthase (FASN), which produces 16‐C saturated fatty acid palmitate. Our work shows that the persistent signaling by mutated EGFR in TKI‐resistant tumor cells relies on EGFR palmitoylation and can be targeted by Orlistat, an FDA‐approved anti‐obesity drug. Inhibition of FASN with Orlistat induces EGFR ubiquitination and abrogates EGFR mutant signaling, and reduces tumor growths both in culture systems and in vivo. Together, our data provide compelling evidence on the functional interrelationship between mutated EGFR and FASN and that the fatty acid metabolism pathway is a candidate target for acquired TKI‐resistant EGFR mutant NSCLC patients.