Aggressive Chronic Lymphocytic Leukemia with Elevated Genomic Complexity Is Associated with Multiple Gene Defects in the Response to DNA Double-Strand Breaks

• Published in: Clinical cancer research Vol. 16; no. 3; pp. 835 - 847
• Main Authors: OUILLETTE, Peter, FOSSUM, Samuel, PARKIN, Brian, LI DING, BOCKENSTEDT, Paula, AL-ZOUBI, Ammar, SHEDDEN, Kerby, MALEK, Sami N
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-02-2010
• Subjects: Antineoplastic agents; Apoptosis - radiation effects; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Cell Cycle Proteins - metabolism; Chromosome Deletion; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 13; CLL; DNA Breaks, Double-Stranded; DNA double-strand break response; DNA-Binding Proteins - metabolism; genomic complexity; Hematologic and hematopoietic diseases; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mutation; Pharmacology. Drug treatments; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Radiation Tolerance; Tumor Suppressor Proteins - metabolism; Double stranded DNA; Chronic lymphocytic leukemia; Lymphoproliferative syndrome; Genomics; Genetics; Malignant hemopathy; Mutation; Genome; Cancer; Complexity; High malignancy
• DOI: 10.1158/1078-0432.CCR-09-2534
• EISSN: 1557-3265
• ISSN: 1078-0432

Purpose: Genomic complexity is present in approximately 15% to 30% of all chronic lymphocytic leukemia (CLL) and has emerged as a
strong independent predictor of rapid disease progression and short remission duration in CLL. We conducted this study to
advance our understanding of the causes of genomic complexity in CLL.
Experimental Design: We have obtained quantitative measurements of radiation-induced apoptosis and radiation-induced ATM autophosphorylation in
purified CLL cells from 158 and 140 patients, respectively, and have used multivariate analysis to identify independent contributions
of various biological variables on genomic complexity in CLL.
Results: Here, we identify a strong independent effect of radiation resistance on elevated genomic complexity in CLL and describe
radiation resistance as a predictor for shortened CLL survival. Furthermore, using multivariate analysis, we identify del17p/p53
aberrations, del11q, del13q14 type II (invariably resulting in Rb loss), and CD38 expression as independent predictors of genomic complexity in CLL, with aberrant p53 as a predictor of ∼50%
of genomic complexity in CLL. Focusing on del11q, we determined that normalized ATM activity was a modest predictor of genomic
complexity but was not independent of del11q. Through single nucleotide polymorphism array–based fine mapping of del11q, we
identified frequent monoallelic loss of Mre11 and H2AFX in addition to ATM , indicative of compound del11q–resident gene defects in the DNA double-strand break response.
Conclusions: Our quantitative analysis links multiple molecular defects, including for the first time del11q and large 13q14 deletions
(type II), to elevated genomic complexity in CLL, thereby suggesting mechanisms for the observed clinical aggressiveness of
CLL in patients with unstable genomes. Clin Cancer Res; 16(3); 835–47