ATMMutations in Major Stereotyped CLL Subsets: Enrichment in Subset #2 is Associated with Unfavourable Outcome

Chronic lymphocytic leukemia (CLL) is a paradigmatic malignancy where the interplay of cell-extrinsic and cell-intrinsic factors has a major impact on disease evolution. Indeed, extrinsic triggering, e.g. antigenic stimulation through the B-cell receptor (BcR), together with intrinsic aberrations, e.g. accumulation of genetic defects, play a major role throughout the natural history of CLL. The importance of antigen involvement is underscored by the existence of 'stereotyped' BcR in up to 30% of CLL patients. Notably, CLL patients with stereotyped BcR can be grouped into different subsets, each with a subset-biased biological and clinical profile. For instance, while the clinically aggressive subset #2 (IGHV3-21/IGLV3-21, comprising both mutated (M-CLL) and unmutated (U-CLL) IGHV genes) displays a remarkably high frequency of SF3B1mutations, subset #8, a subset with the highest risk of Richter transformation, shows a strong association with trisomy 12 and NOTCH1mutations. ATMdefects are implicated in the evolution of CLL and are associated with a dismal prognosis, however the extent to which they contribute to the genetic landscape in stereotyped subsets remains unexplored.