Abstract 3428: Aging, telomere and TP53: a potential biological insight into the mechanistic origin of acute lymphoblastic leukemia (ALL) in the elderly
Authors: Zakout Ghada , Rai Lena , Fielding Adele K. 
Published: August 2015

Telomere attrition is a recognized feature of genomically unstable cancer genomes prevalent in older patients. Unchecked genomic instability secondary to loss of TP53 fosters telomere attrition. The relevance of this in older ALL patients has not been studied. Population based cytogenetic study of adults with ALL demonstrated that aneuploidy - reflecting genomic instability - was almost 4 fold more common in those ≥60 years than in younger counterparts. Preliminary data from a UK cohort of patients with ALL aged ≥60 years revealed a significantly higher rate of copy number alterations (CNA) (mostly comprising of deletions of key B-cell differentiation/cell-cycle genes, recognized for their proximity to recombination sequence motifs) when compared to their younger counterparts. Correlative cytogenetic analysis notably revealed 28% of such alterations were attributed to gross chromosomal losses rather than true intragenic deletions in the over 60s versus 10% in the under 35s suggesting an alternative, potentially age-related, non-RAG-mediated driver for some of such aberrations. We hypothesize that permissive telomere shortening is a driver. We assessed relative telomere length (RTL) using monochrome multiplex quantitative PCR of remission DNA samples of ALL patients aged ≥60 and compared it with younger counterparts aged &lt;35. There was a significant age-related reduction in RTL; mean RTL for those aged &lt;35 and ≥60 years with ALL was 1.38 and 0.6. RTL of remission DNA from ≥60 years ALL patients was significantly shorter than that of age-matched controls without ALL; mean 0.6 versus 1.07, p&lt;0.01. We then assessed leukemic DNA RTL and compared it to that of matched remission DNA to define leukemic telomere state, expressed as log2 ratio, in patients aged ≥60 (N = 29) and &lt;35 years (N = 35). Mean log2 ratio was significantly higher in the ≥60s than in the &lt;35s (1.009 and -0.7498, p = 0.0002). Based on a log2 ratio cut-off of 3.18 derived from expectation maximization-mixture guided model to define leukemic telomere gain or loss, 8 patients (27.6%) aged ≥60 had leukemic telomere gain whereas none of those aged &lt;35 years had gain. Leukemic telomere gain was statistically associated with more CNA of 8 key B-cell differentiation/cell-cycle genes assessed by multiplex ligation probe amplification P335-ALL IKZF1 kit (median 4 versus 1 with loss, p&lt;0.01) and hypodiploid/near triploid or complex karyotypes (5/8 versus 1/13 with loss, p&lt;0.01). TP53 alteration assessed by cytogenetics, FISH +/- direct sequencing of exons 5-8 in the ≥60 ALL cohort was noted in 5/8 patients with gain versus 4/17 with loss; p = 0.037. Whilst our study is currently limited by sample size integration of CNA with telomere features of the ALL genome and TP53 state has revealed a potential interactive link between aging, telomere attrition and TP53-dependent adaptive response loss which provides the first insight into disease biology of elderly ALL.

Citation Format: Ghada Zakout, Lena Rai, Adele K. Fielding. Aging, telomere and TP53: a potential biological insight into the mechanistic origin of acute lymphoblastic leukemia (ALL) in the elderly. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3428. doi:10.1158/1538-7445.AM2015-3428