Abstract 2539: Antiapoptotic gene expression signature reveals a combined talk to prevent apoptosis: A model to choose the proper BH-3 mimetic drug
Authors: Jacopo Nanni, Giorgia Simonetti, Samantha Bruno, Giovanni Marconi, Maria Chiara Fontana, Cristina Papayannidis, Maria Chiara Abbenante, Lorenzo Montanaro, Michele Cavo, Giovanni Martinelli
Journal: Cancer Research (2018)

Abstract BACKGROUND: Apoptotic regulation involves several actors which can have a positive and negative effect and may represent a target for personalized therapy. Nowadays, BCL-2 inhibitors have successfully passed preliminary phases of clinical experimentation, however the involvement of other essential proteins could represent a resistance mechanism to BCL-2 inhibitors and reveal novel therapeutic targets in acute myeloid leukemia (AML). Our study aim to investigate the expression of anti-apoptotic genes in AML patients. METHODS: We performed Human Transcriptome Array 2.0 (Affymetrix) in a cohort of 59 newly diagnosed AML. K-means clustering has been used to categorize patients in different cluster. A pool of 7 healthy donors was used to normalize expression data. Survival analysis was conducted with Kaplan-Meyer method and differences in survival were assessed with Log-Rank test. RESULTS: BCL-2, MCL-1 and BCL2L1 gene expression values in 59 AML patients allowed us to establish 5 clusters (Fig. 1a): cluster 1 with the overexpression of MCL1, cluster 2 with low expression of all analyzed genes; cluster 3 with overexpression of BCL2L1, cluster 4 with overexpression of BCL-2 and cluster 5 with high values of expression of all 3 genes. Clusters 2 and 5 included the majority of patients (40/59, 68%). Furthermore, the 3-D Scatter Plot allowed us to observe how patients out of the central cloud (Clusters 2-5) always presented an overexpression of one out of the three anti-apoptotic genes. Moreover, when BCL-2 level is low (Cluster 1-2-3), MCL-1 and BCL2L1 levels are high, respectively. In term of overall survival (OS), there were no statistically significant difference between Cluster 1-3-4, where one different anti-apoptotic gene is always overexpressed. Finally, analyzing the impact of BCL-2 expression on OS in a cohort of 36 young patients treated with chemotherapy, those with high expression of the three antiapoptotic genes had worse outcome (p=0.07). CONCLUSION: BCL-2, MCL-1 and BCL2L1 expressions are quite balanced in AML patients evaluated. One out of the three genes is often overexpressed, confirming the key role of anti-apoptotic genes in leukemogenesis. Even though BCL-2 expression influence patients chemosensitivity, MCL-1 and BCL2L1 overexpression has been documented when BCL-2 is normally or downregulated. In conclusion, we suppose that BCL-2 inhibitors resistance may be caused by MCL-1 and BCL2L1 overexpression. Finally, a combined approach should be realized to switch-off leukemic anti-apoptotic mechanisms. Gene expression profile could provide a synthetic lethal instrument to choose the proper BH3-mimetic drug or combination. Supported by: ELN, AIL, AIRC, project Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project, HARMONY project, Fondazione del Monte BO e RA project. Citation Format: Jacopo Nanni, Giorgia Simonetti, Samantha Bruno, Giovanni Marconi, Maria Chiara Fontana, Cristina Papayannidis, Maria Chiara Abbenante, Lorenzo Montanaro, Michele Cavo, Giovanni Martinelli. Antiapoptotic gene expression signature reveals a combined talk to prevent apoptosis: A model to choose the proper BH-3 mimetic drug [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 2539.