Identification of two epitypes of IGHV unmutated chronic lymphocytic leukemia with distinct B‐cell‐related epigenetic imprinting and genetic alterations

Chronic lymphocytic leukemia (CLL), the most frequent leukemia in the Western world, is characterized by extensive biological and clinical heterogeneity. 1 Immunogenetic, genetic, and epigenetic features have been described as major molecular traits strongly associated with clinical impact in CLL. 2 The levels of somatic hypermutation (SHM) of the immunoglobulin heavy chain variable (IGHV) region segregate cases into IGHV unmutated and mutated CLLs (U-CLL and M-CLL, respectively), being the former clinically more aggressive.1 This dichotomous classification was further refined using DNA methylation imprints of normal B-cell maturation, leading to the identification of three distinct epigenetic subtypes or epitypes, including naive-like/lowprogrammed CLL (n-CLL), mostly corresponding to U-CLL, intermediate CLL and memory-like/high-programmed CLL, both of which belonging to M-CLL.3,4 In spite of this classification into three categories, a model in which CLLs derive from a continuum of mature B-cell maturation stages was proposed, suggesting that CLL could be potentially stratified into additional epitypes.4 Apart from this link with normal B-cell maturation, the DNA methylome of CLL also reflects the past proliferative history and presents specific DNA methylation signatures related to its pathogenesis.5,6 In addition to IGHV subtypes and epitypes, specific genetic lesions and the presence of complex karyotypes (CKs) carry prognostic 1,2,7,8 and predictive value.9 Such CK has been frequently but not always associated with U-CLL and alterations affecting the HemaSphere.