We have provided a tentative model of the nature and origin of CLL cell. Such a model is based upon four major considerations. First, a number of phenotypic, functional, and molecular data indicate that the B-CLL cell is a B cell characterized by several T-cell-associated features. We take these data to suggest that the early transforming event may occur early in the lymphocyte ontogeny, likely in a lymphoid progenitor endowed with some sort of bipotential possibility (B and T). Second, the transformed precursor must have the capacity to differentiate into a mature B cell whose functional BCR may allow Ag intervention to trigger clonal expansion. The implication is that the two subsets of the disease, defined by their IgVH genes mutational status, have a different Ag reactivity. Mutated cases seem to have a lower capacity to interact with Ag and behave as anergic cells with low proliferative potential. Unmutated cases likely undergo repeated rounds of Ag stimulation, which causes repeated cycles of replication and the inherent risk of acquiring chromosomal aberrations. The third consideration is that all relevant events of the natural history of CLL occur in tissues where the balance between proliferation and reduced apoptosis is influenced by the leukemic cell capacity to respond to the proliferative and anti-apoptotic microenvironmental signals provided by tissue bystander cells through cellular contacts and soluble factors. Finally, the existence of monoclonal CLL-like B lymphocytes in the peripheral blood of otherwise healthy adults may provide a clue to better understand the nature and origin of CLL cell.
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