Clonal succession and deletion of bcr/abl sequences in chronic myelogenous leukemia with recurrent lymphoid blast...

The development of cancer is generally believed to occur by a multistep process in which critical genetic defects accumulate in a clone of cells, confer a growth advantage, and result in the emergence of more malignant subclones. This paper describes the clonal origin of cells in a patient with Philadelphia-chromosome negative, M-bcr rearrangement-positive chronic myelogenous leukemia, observed in two episodes of lymphoid blast crisis (BC), the intervening chronic phases (CP), and following allogeneic bone marrow transplantation. Serial analysis of immunoglobulin heavy and kappa light chain (IgJH, IgCK), beta-T-cell receptor (beta-TcR) and bcr major breakpoint cluster region (M-bcr) gene rearrangements was performed. Clonal IgJH rearrangements present in cells of the first lymphoblastic crisis (BC1) were altered during the chronic phase post-treatment (CP1), and were again altered in recurrent blast crisis (BC2). In addition, the M-bcr gene rearrangement present in BC1 and CP1 was absent from cells in BC2. These observations suggest that the course of clinical neoplastic disorders may not always be characterized simply by a hierarchical process of clonal evolution, but may also involve clonal succession of malignant cells. Moreover, the deletion of M-bcr in recurrent BC suggests that bcr/abl may not be essential for the maintenance of cell growth in established BC.