We report 2 novel, cryptic chromosomal abnormalities in precursor B-cell acute lymphoblastic leukemia (BCP-ALL): a translocation, either t(X;14)(p22;q32) or t(Y;14)(p11; q32), in 33 patients and an interstitial deletion, either del(X)(p22.33p22.
CLL with 11q deletion can be divided into two subgroups based on the integrity of the residual ATM allele. Patients with complete loss of ATM function, due to biallelic ATM defects, have defective responses to cytotoxic chemotherapeutics in vitro and a poorer clinical outcome. ATM mutant subclones can develop during an individual's disease course and give rise to additional expansion of the 11q deleted subclone.
Clinical trials have been initiated with Apo2L/TRAIL (Genentech) and agonistic mAbs to TRAIL receptors, -R1 and -R2 (Human Genome Sciences). The apoptosis-inducing ability of these mAbs and different TRAIL preparations, in the presence or absence of histone deacetylase inhibitors (HDACi), varied markedly against primary chronic lymphocytic leukaemia (CLL) cells and various tumor cell lines, demonstrating an unanticipated preferential apoptotic signaling via either TRAIL-R1 or -R2. Contrary to literature reports that TRAIL-induced apoptosis occurs primarily via signaling through TRAIL-R2, CLL cells, in the presence of HDACi, undergo predominantly TRAIL-R1-mediated apoptosis. Consequently, Apo2L/TRAIL, which signals primarily through TRAIL-R2, is virtually devoid of activity against CLL cells. To maximize therapeutic benefit, it is essential to ascertain whether a primary tumor signals via TRAIL-R1/-R2, prior to initiating therapy. Thus combination of an agonistic TRAIL-R1 Ab and an HDACi, such as the anticonvulsant sodium valproate, could be of value in treating CLL.
) and 8q22.3 (rs2511714, P=2.90x10 -9 ). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL.
Speedy et al
3Chronic lymphocytic leukemia (CLL) is the most common hematological malignancy in Western countries 1 and is characterized by a 8-fold increased risk in first-degree relatives 2 . Genome-wide association studies (GWASs) have so far identified common variants at 24 loci that contribute to the heritable risk of CLL [3][4][5][6] . Current projections for the number of independent regions harboring common variants associated with CLL suggest that additional risk loci conferring modest effects should be identified by expansion of discovery GWAS datasets.To identify additional novel susceptibility loci for CLL, we conducted an independent primary scan of CLL and performed a genome-wide meta-analysis with a previously published GWAS followed by analysis of the top single nucleotide polymorphisms (SNPs) in two separate case-control series.In the primary scan (UK-CLL-2), 1,271 CLL cases were genotyped using the Illumina Omni Express Figure 1). To harmonize the two GWAS datasets, we imputed UK-CLL-1 to recover untyped SNPs directly genotyped in UK-CLL-2, using data from the 1000 Genomes Project as reference. Using data on all cases and controls from each GWAS, we derived joint odds ratios (ORs) and confidence intervals (CIs) under a fixed effects model for each SNP and associated P-values, restricting analysis to SNPs with MAF >1%. After filtering on the basis of pre-specified quality-control measures Table 2). We also identified promising association signals (i.e.
P<1.0×10−5 ) at 11 additional loci (Supplementary Table 2). We applied 1000 Genomes imputation to UK-CLL-1 and UK-CLL-2 at these loci to investigate if a statistically significant stronger SNP association could be identified, recovering an additional SNP which was significant at the genome-wide threshold (rs6858698; Supplementary Table 2). We performed replication genotyping of six SNPs selected on the basis of statistical significance (rs2236256, rs6062501, rs6858698) and gene centricity coupled with Table 4). While we found no evidence for a relationship between rs10936599, and telomere length in 246 CLL patients (Supplementary Table 5), carrier status for the rs10936599-C risk allele is previously been associated with significantly longer telomeres in leukocytes 10,11 .The third significant association was at rs6858698 on 4q26 (OR=1.31, 95% C.I. 1.20-1.44; P=3.07x10 linked to cis-platinum resistance by enhancing apoptosis. A recent GWAS of CLL has reported promising associations at 5p15.33 defined by rs10069690 and at 8q22.33 defined by rs2511714 6 . Combining the Pvalues for rs10069690 and rs2511714 obtained in our meta-analysis (P=1.0x10 -4 and 1.0x10respectively) with published data 6 provides robust evidence for both associations (combined P-values 1.10x10 -10 and 2.90x10 -9 respectively; Supplementary Figure 4). rs10069690 maps to intron 4 of TERT (telomerase reverse trans...
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