Model of clonal diversification and selection in CLL. (A) Locally disordered DNA methylation is higher in CLL and cancer tissues compared with normal tissues, including B cells (adapted from Landau et al18 ); (B) Adverse impact of locally disordered DNA methylation on failure-free survival18 ; (C) Clonal diversification may result from synergic effects of disordered DNA methylation and genomic instability (left). Clonal selection related to therapeutic and microenvironment pressure shapes the subclonal composition that ranges from clonal equilibrium to clonal competition (right). High level of clonal diversification could lead to the emergence of fitter subclones competing within CLL bulk and is responsible for more aggressive/resistant disease associated with poor survival.
