CLL Progression Is Associated with Increased Clonal Diversity and Replication Stress

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Colleges, School and Institutes

External organisations

  • West Midlands Regional Genetics Laboratory
  • Birmingham Women's NHS Foundation Trust

Abstract

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 is known about the mechanisms which contribute towards genomic instability and clonal diversification during CLL progression. Genomic instability is a major cause of subclonal diversification and can be driven by replication stress (RS). It has been shown that in solid tumours RS drives tumourigenesis through the following steps: presence of unreplicated DNA, accumulation of DNA damage, activation and functional loss of ATM/p53 and genomic instability. In this study we addressed whether high proliferation rates during CLL progression are associated with increased subclonal diversification and with RS. We compared samples from the indolent and progressive stages of CLL, both in individual patients and in patient cohorts. We determined clonal diversification by two complementary methods: multiplexed-FISH and next generation sequencing (NGS). We measured RS by an assay that recognizes a region of unreplicated DNA.

Details

Original languageEnglish
Title of host publicationBlood
Publication statusPublished - 6 Dec 2014

Publication series

NameBlood
PublisherAmerican Society of Hematology
ISSN (Print)0006-4971