ATM function and its relationship with ATM gene mutations in chronic lymphocytic leukemia with the recurrent deletion (11q22.3-23.2)

Abstract

Approximately 10–20% of chronic lymphocytic leukemia (CLL) patients exhibit del(11q22–23) before treatment, this cohort increases to over 40% upon progression following chemoimmunotherapy. The coding sequence of the DNA damage response gene, ataxia-telangiectasia-mutated (ATM), is contained in this deletion. The residual ATM allele is frequently mutated, suggesting a relationship between gene function and clinical response. To investigate this possibility, we sought to develop and validate an assay for the function of ATM protein in these patients. SMC1 (structural maintenance of chromosomes 1) and KAP1 (KRAB-associated protein 1) were found to be unique substrates of ATM kinase by immunoblot detection following ionizing radiation. Using a pool of eight fluorescence in situ hybridization-negative CLL samples as a standard, the phosphorylation of SMC1 and KAP1 from 46 del (11q22–23) samples was analyzed using normal mixture model-based clustering. This identified 13 samples (28%) that were deficient in ATM function. Targeted sequencing of the ATM gene of these samples, with reference to genomic DNA, revealed 12 somatic mutations and 15 germline mutations in these samples. No strong correlation was observed between ATM mutation and function. Therefore, mutation status may not be taken as an indicator of ATM function. Rather, a direct assay of the kinase activity should be used in the development of therapies.

A reduced panel of eight genes (ATM, SF3B1, NOTCH1, BIRC3, XPO1, MYD88, TNFAIP3, and TP53) as an estimator of the tumor mutational burden in chronic lymphocytic leukemia

“… 31 Even if the relationship between ATM mutations and function is not strong, the residual ATM allele is frequently mutated in patients with ATM deletion and is associated with poorer response to chemotherapy. 32 , 33 Being part of the integrated mutational and cytogenetic score of Rossi et al, 10 NOTCH1 and BIRC3 alterations are poor prognosis genetic markers. Clonal and subclonal NOTCH1 mutations are associated with trisomy 12 34 and predict shorter TFS.…”

Drug-free macromolecular therapeutics induce apoptosis in cells isolated from patients with B cell malignancies with enhanced apoptosis induction by pretreatment with gemcitabine

“…23 Deletion of 11q occurs in 10-20% of CLL patients. 25 The 11q22 region is involved in activation of p53-dependent apoptosis pathway thus its loss leads to reduced cell death. 23 Combination of deletions of 17p and 11q are considered as significantly poorer prognoses.…”

Detection of 13q deletion in patients with chronic lymphocytic leukemia and its correlation to hematopathological parameters

“…There are many factors that help to predict the patient outlook. There are variable Classical prognostic markers that have been identified in CLL which include the following (56) .…”

“…The biology behind the better prognosis of women is not as yet obvious. The proportion of CLL with mutated IGHV genes is higher in females, and this may provide a possible explanation (56).…”