Extreme telomere erosion in ATM-mutated and 11q-deleted CLL patients is independent of disease stage

Abstract

with chromosomal abnormalities, and about half of them carry FLT3-ITD. Chronic phase CML is NPM1 wt , whereas only one case of NPM1 mut myeloid blast crisis CML has been reported. 10 IDH1 and IDH2 mutations are also not found in chronic phase CML but can be found at low frequency in blast crisis CML. 11 Here, we present a CML patient who developed clonal hematopoietic disease (AML) in PhÀ cells, with normal karyotype and NPM1 mut , while being in complete CML molecular remission and without previous MDS phase or CCA/PhÀ. The development of PhÀ AML could be the result of inherent genomic instability or a direct effect of TKI therapy, whereas the possibility that AML occurred by chance cannot be excluded. It is should be stressed that sensitive RQ-PCR assay could detect NPM1 mut transcripts 1 year before overt AML, implying that the development of NPM1 mut AML was a slow process. He relapsed twice with clonal evolution: IDH2 R140Q mutation at first relapse and complex karyotype at second relapse. To our knowledge, this is the first report of normal karyotype NPM1 mut AML in PhÀ cells in CML complete remission during imatinib treatment.

Telomere dysfunction and its role in haematological cancer

“…Consistent with this view, BrittCompton et al (2011) showed that in comparison to patients who have wild type ATM gene, TLs were significantly shorter in CLL patients with ATM mutations including those with stage A disease. This TL shortening was present in both patients with ATM mutations and 11q deletions and was independent of IGHV gene mutation status, CD38 status and ZAP70 status (Britt-Compton et al, 2011). This provides evidence that defective double-strand break checkpoints, which are known to exist in ATM mutated cells, may lead to extended replication and extreme telomere shortening.…”

ATM mutation rather than BIRC3 deletion and/or mutation predicts reduced survival in 11q-deleted chronic lymphocytic leukemia: data from the UK LRF CLL4 trial

“…2,3 Subsequent studies have documented associations with unmutated IGHV genes, del13q, genomic complexity, short telomeres, progressive disease and a poor outcome in response to alkylating agent or purine analog treatment, which was improved by their use in combination and ameliorated by the further addition of rituximab. [4][5][6][7][8][9][10] Genomic profiling studies have refined previous karyotypic and FISH studies showing that 11q deletions are mono-allelic, frequently large and include a minimally deleted region (MDR), which encompasses the ATM gene. [11][12][13][14] Evidence that ATM is a key target of 11q deletions is derived from findings that: 1) mutation of the ATM gene is found in 30-40% of patients with an 11q deletion; 15,16 2) the presence of an ATM mutation results in impaired DNA damage responses; 15,[17][18][19] and 3) patients in the UK LRF CLL4 trial with biallelic ATM abnormalities (deletion and mutation) have a poorer outcome following the initial therapy with alkylating agent and/or purine analog therapy compared to those with mono-allelic ATM deletion or mutation.…”

ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset #2 is associated with markedly short telomeres

“…This study further reinforces the recent suggestion that CLL development is driven by antigenic selection linked with preferential acquisition of specific genetic defects during disease evolution. Stavroula Ntoufa, 4 Zadie Davis, 5 Gunnar Juliusson, 6 Karin E. Smedby, 7 Chrysoula Belessi, 8 Panagiotis Panagiotidis, 9 Tasoula Touloumenidou, 4,10 Frederic Davi, 11 Anton W. Langerak, 12 Paolo Ghia, 13 Jonathan C. Strefford,14 David Oscier, 5 Jiri Mayer, 1 Kostas Stamatopoulos, 4 Sarka Pospisilova, 1,2 Richard Rosenquist, 3 and Martin Trbusek…”

“…The prognostic relevance of TL in CLL has been repeatedly reported 9,10 and CLL cells with ATM mutations were recently shown to display extreme telomere shortening, allowing telomere fusions and subsequent large-scale genomic rearrangements facilitating disease progression through increased A B genomic instability. 11,12 Relative telomere length (RTL) was investigated by real-time quantitative PCR as originally described by Cawthon et al 13 with certain modifications (Online Supplementary Appendix). The median RTL value 0.4 (range 0.05-2.25) was subsequently used to distinguish between 'short' and 'long' telomeres.…”