Purine analogue triggers DNA lesions and oncogenic stress which in turn activate DNA repair pathways and apoptosis of leukemic cells. CK which reflects a genetic instability is probably the consequence of a defective DNA repair pathway. Consequently, when components of DNA repair signaling such as TP53, ATM (1-2) or ribosomal proteins 15 (RPS15) (3) are deteriorated; patients are more refractory to fludarabine-based therapeutical approaches. Conventional cytogenetic provides a pan-genomic information about instability and clonal architecture. This information is not available with FISH but requires the expertise of a cytogeneticist, which is not available in all centers. SNP array is also interesting because it is a more sensitive approach to overcome the genomic instability and clonal diversity of progressive or fludarabine-refractory patients (4-5). More recent technological approaches such as next generation sequencing (6) and microarrayed single-cell sequencing (7) allow for better approach of the diversity of clonal architecture and the presence of subclones with strong prognostic impact with regard to clinical evolution and sensitivity to treatment. All these new techniques are not yet available daily but provide new possibilities for the future to identify high risk CLL patients. In the meantime, the identification of CK generates useful prognostic information.
Written by: LE BRIS Yannick
(1) J Hematol Oncol. 2016 Sep 15;9(1):88. Extensive next-generation sequencing analysis in chronic lymphocytic leukemia at diagnosis: clinical and biological correlations. Rigolin GM, et al.
(2) J Clin Oncol. 2007 Dec 1;25(34):5448-57. Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion. Austen B et al.
(3) Blood. 2016 Feb 25;127(8):1007-16. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations.
Ljungström V et al.
(4) Cancer Genet. 2011 Dec;204(12):654-65. Clonal diversity analysis using SNP microarray: a new prognostic tool for chronic lymphocytic leukemia. Zhang L et al.
(5) Ann Oncol. 2013 May;24(5):1378-84. Large genomic aberrations detected by SNP array are independent prognosticators of a shorter time to first treatment in chronic lymphocytic leukemia patients with normal FISH. Mian M et al.
(6) Blood. 2016 Apr 28;127(17):2122-30. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Nadeu F et al.
(7) Nat Commun. 2016 Oct 14;7:13182. Massive and parallel expression profiling using microarrayed single-cell sequencing. Vickovic S et al.
Read the Abstract