{'fraction_non_alphanumeric': 0.03664059283655825, 'fraction_numerical': 0.0354055166735282, 'mean_word_length': 4.855421686746988, 'pattern_counts': {'":': 0, '<': 2, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
The selectivity of Marinopyrrole A to induce apoptosis in MCL1high BCL2low expressing myeloma cells is related to its ability to impair protein translation

Multiple myeloma (MM) is an incurable plasma-cell malignancy that is heterogeneous in its clinical presentation and prognosis. The gene expression profile of patients led to the molecular classification of MM patients into different disease subtypes, which takes into account the presence of primary IGH translocations and the universal over-expression of the cyclin D genes. The main translocation subtypes include t(11;14), t(4;14) and t(14;16) with an over-expression of CCND1, WHSC1 (MMSET) and MAF genes, respectively. The notion of MM heterogeneity has been extended to the BCL2 family content in each MM subgroup. Indeed, we have previously shown that the combined profile of BCL2, BCL2L1 (BCLXL) and MCL1 was sufficient to distinguish MM molecular groups (Gomez-Bougie & Amiot, 2013). Namely, MAF and WHCS1 groups can be distinguished from hyperdiploid and Cyclin D1 (CCND1) groups by a low expression of BCL2 and high MCL1 expression. Of note, WHSC1 and MAF subgroups are known to be of poor prognosis (Chesi & Bergsagel, 2013) highlighting the importance of targeting MCL1. We assessed the capacity of Marinopyrrole A, a new class of MCL1 inhibitor (Doi et al, 2012), to elicit apoptosis across a large collection of human MM cell lines (HMCLs) (n = 20) encompassing the main molecular myeloma subtypes and well characterized for BCL2 family gene and protein expression (Bodet et al, 2011). As previously described, we have authenticated each cell line used in this study by a flow cytometry-based barcode (Table SI). The median lethal dose (LD50) values of Marinopyrrole A was defined as the concentration sufficient to kill 50% of cells after 48 h of treatment. Cell lines displayed LD50 ranging from 0 7 to 11 lmol/l (Table SI). Marinopyrrole A efficiency was analysed according to the BCL2 family gene expression. We found that not only a high expression of MCL1 (P < 0 04, q = 0 45) but also a low expression of BCL2 (P < 0 0002, q = 0 63) correlated with Marinopyrrole A LD50s (Fig 1A). These results suggest that the sensitivity of Marinopyrrole A was strongly dependent on BCL2 family protein expression. Analysis of the main myeloma subgroups showed that the CCND1 HMCLs were significantly less sensitive (median LD50 4 12 lmol/l) than the other MAF and