CLL Progression Is Associated with Increased Clonal Diversity and Replication Stress

摘要: There is increasing evidence to suggest that genetic lesions accumulate during CLL progression, often involving mutations in DNA damage response genes ATM and TP53, or SF3B1. However, little known about the mechanisms which contribute towards genomic instability clonal diversification progression. Genomic a major cause of subclonal can be driven by replication stress (RS). It has been shown solid tumours RS drives tumourigenesis through following steps: presence unreplicated DNA, accumulation damage, activation functional loss ATM/p53 instability. In this study we addressed whether high proliferation rates progression are associated with increased RS. We compared samples from indolent progressive stages CLL, both individual patients patient cohorts. determined two complementary methods: multiplexed-FISH next generation sequencing (NGS). measured an assay recognizes region DNA. Using identifies location multiple alterations at single cell level, identified 3/11 relapsed occurrence novel subclones (11q) TP53 (17p) deletions were not observed pre-treatment tumours. These findings corroborated targeted NGS recurrently mutated revealed carrying ATM, NOTCH1, SF3B1 BIRC3 time relapse 9 out 22 paired samples. Of particular interest was acquisition gene four patients. data demonstrate intrinsic propensity for Having demonstrated association between disease sought identify mechanism behind phenomenon. results under-replicated sequestered into nuclear compartments marked 53BP1 protein. Therefore, appearance bodies G1-cells represents marker present PBMCs healthy individuals, 20 stage contained low level marker. This stark contrast elevated proportion cells 13 (p Collectively, our indicate correlates may provide diversification. Disclosures No relevant conflicts declare.