Recent advances in the molecular pathogenesis of lymphomas.

Most human lymphomas remain heterogeneous biologic entities in spite of recent advances in the description of their clinical presentation, cellular morphology, immunophenotype, and genotype. Elucidation of genetic alterations causing malignant transformation may explain pathogenesis, refine differential diagnosis, clarify prognosis, and provide rational basis for new therapy. During the last year the expression of anaplastic lymphoma kinase clarified presentation and provided clues toward the outcome of anaplastic large cell lymphoma; the breakpoints of t(2;5) were mapped; constitutive activation of anaplastic lymphoma kinase by a chromosomal inversion was described; transformation was shown to be independent of nuclear localization of anaplastic lymphoma kinase; and phospholipase C-gamma was identified as a molecular target for the kinase activity of anaplastic lymphoma kinase. Molecular characterization of recurrent chromosome abnormalities has identified new candidate oncogenes: bcl-9, bcl-10, PAX-5, MMSET, and c-maf. Their precise role in malignant transformation, and the frequency of their alteration in lymphoma and myeloma, is not yet defined. The expression of the antiapoptotic protein bcl-2 on aggressive lymphomas was shown to be associated with inferior disease-free survival by several investigators. This may be a target of pharmacologic reduction of bcl-2 levels. Can these advances in molecular pathogenesis improve cure rates for lymphoma? The spectacularly successful molecular modeling of inhibitors for HIV protease suggests that this may be an attainable objective.