The progressive evolution from antigen (Ag) stimulation to molecular abnormalities in the natural history of CLL. MBLs are vastly more common than CLLs, and only a tiny fraction of CLLs progress into more advanced stages of the disease or evolve into Richter syndrome or undergo prolymphocytoid transformation. Shaded triangle represents the progressively decreasing size of individual situations. HSCs of CLL patients have been suggested to carry intrinsic abnormalities and to be skewed toward B-cell lineage (top left corner). The encounter of such a B cell with an appropriate external stimulus (here exemplified with the antigen/BCR interaction) triggers the clonal development of MBLs, probably enhancing the cell stimulation. The possibility exists (bottom left corner) that external stimulation may precede the appearance of genetic anomalies. Over time, the pressure of (eg, antigenic) stimulation leading to enhanced proliferation favors the acquisition of (initial or additional) genetic abnormalities, and some MBLs may progress into overt CLL. If and when the acquired genetic abnormalities (eg, recurrent mutations) are able to substitute the necessity of external stimulation by impinging on the same final pathway(s), a more aggressive version of CLL is acquired (either in the form of refractory disease or of Richter syndrome or of prolymphocytoid transformation).