Multiple myeloma (MM) is still an incurable hematological malignancy. Despite recent progress due to new anti-myeloma agents, the pathology is characterized by a high frequency of de novo or acquired resistance. Delineating the mechanisms of MM resistance is essential for therapeutic advances. We previously showed that long-term genotoxic stress induces the establishment of a senescence-associated secretory phenotype, a pro-inflammatory response that favors the emergence of cells with cancer stem-like properties. Here, we studied the short-term response of MM cells following treatment with various DNA damaging agents such as the energetic C-ion irradiation. MM cells are highly resistant to all treatments and do not enter apoptosis after they arrest cycling at the G2 phase. Although the DNA damage response pathway was activated, DNA breaks remained chronically in damaged MM cells. We found, using a transcriptomic approach that RAD50, a major DNA repair gene was downregulated early after genotoxic stress. In two gerosuppression situations: induction of hypoxia and inhibition of the mammalian target of rapamycin (mTOR) pathway, we observed, after the treatment with a DNA damaging agent, a normalization of RAD50 expression concomitant with the absence of cell cycle arrest. We propose that combining inhibitors of mTOR with genotoxic agents could avoid MM cells to senesce and secrete proinflammatory factors responsible for cancer stem-like cell emergence and, in turn, relapse of MM patients.
4593 Introduction: As deletion of 17p13 (del 17p13) in Chronic lymphocytic leukemia (CLL) patients is associated with poor outcome and chemorefractoriness to alkylating agents and purine analogues, current diagnostic guidelines recommend its screening at diagnosis and prior to treatment initiation. TP53 is a tumor suppressor gene, maps to 17p13 and is inactivated through somatic mutations or by 17p13 deletion. Recent studies show that TP53 mutation is of clinical relevance in CLL patients and has practical implication for therapeutic stratification. The purpose of this study is to characterize the TP53 mutation pattern and its incorporation into treatment algorithms in CLL patients treated in our center. Materials and methods: A retrospective study was performed on a cohort of 42 patients with CLL for whom clinical, biological and fluorescent in situ hybridization (FISH) data were available. Ages ranged from 31 to 88 (median, 63 years), 17 patients were in Binet stage A, 12 in B and 13 in stage C. Treatment was not in controlled trials, and standard clinical criteria were used for the initiation of therapy. DNA was extracted from 52 available samples and TP53 exons 2 to 11 were screened for mutations by high resolution melting (HRM) (Roche LC480). Mutations were confirmed by sequencing both strands using different primer sets (Beckman, Ceq 8000) then validated by the IARC and UMD TP53 Mutation Databases. Results: Out of 42 patients, del 17p13 was observed in 11 (26%), del 11q22 in 8 (19%), del 13q14 in 13 (31%), trisomy 12 in 2 (5%) and normal FISH in 20 (47.6%). We found an overall incidence of TP53 mutations of 19% (8 of 42 patients), 1 new mutation was identified and 5 mutations were not previously reported in CLL but in other cancers according to the IARC and UMD TP53 mutation Databases (table 1). A total of 65 polymorphisms were detected with a prevalence for the g.11446C>G polymorphism of 0.9 compared to 0.49 in published data. Amongst the 8 patients with TP53 mutations, 7 (87%) presented a 17p deletion and mutations were mainly located in the DNA binding domain (62%). 7 of 11 patients (63%) with 17p13 deletion harbored a TP53 mutation. In the absence of del 17p13 only 3% of patients (1 of 31) had a TP53 mutation (table 2). 5 of 8 patients with mutations (62%) presented with an advanced clinical stage and a median age of 56 years. Clonal evolution leading to acquisition of the TP53 mutation was not necessary related to therapy; 3 sequential samples were available for a patient with no abnormalities at diagnosis and who developed a TP53 mutation after 2 years and before therapy initiation. Another patient who was initially devoid of TP53 mutations and responded to treatment with standard chemotherapy, developed chemorefractoriness concomitant with a TP53 mutation acquisition. An interesting case was that of a patient who had been in complete remission after treatment with rituximab, fludarabin and cyclophosphamid (RFC) despite the presence of a TP53 mutation without del 17p13 at diagnosis. Sequencing demonstrated that this patient harbored a silent mutation in exon 4 g.12441C>G. In Conclusion: This study shows similar findings to published data except for a higher incidence of patients with TP53 mutations probably due to bias selection and a low cohort of patients. We identified a new mutation and 5 other mutations not previously detected in CLL patients. As TP53 is associated with poor outcome and chemorefractoriness, and its acquisition might be a result of positive pressure selection following treatment, we think it is of utmost importance to look for TP53 mutations in parallel to FISH at diagnosis and in case of chemorefractoriness using the HRM a cheap and sensitive method followed by sequencing positive cases. Disclosures: No relevant conflicts of interest to declare.
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