The evolving contribution of hematopoietic progenitor cells to lymphomagenesis.

Recent genomic studies have outlined a landscape of recurrent alterations within some subtypes of lymphoid cancer. Yet, the timing and cellular contexts during which these alterations occur (ie, the molecular ontogeny) remain poorly understood. Lymphoid malignancies offer an exceptional opportunity to delineate the ontogeny of somatic alterations, as lymphocyte differentiation absolutely requires the introduction of indelible genetic rearrangements at antigen receptor loci during specific stages of maturation. We review competing models of lymphomagenesis and highlight evolving evidence that somatic alterations in uncommitted hematopoietic progenitors contribute to some mature lymphoid neoplasms. These progenitors could serve as reservoirs for further clonal evolution and thereby contribute to therapeutic resistance, tumor relapse, and the development of second hematologic malignancies. Defining the pathways that are dysregulated within early progenitors and the ontogeny of subsequent alterations that contribute to lymphoid transformation could establish novel therapeutic targets across a variety of hematologic malignancies and even guide avenues for future preventive strategies.