Change in IgHV Mutational Status of CLL Suggests Origin From Multiple Clones

Immunoglobulin heavy chain mutational status of chronic lymphocytic leukemia is used to predict outcome, and is considered stable over time. We examined mutational status in a 56 patients cohort study, and identified 7 who changed mutational status. This supports the multiclonal nature of chronic lymphocytic leukemia and suggests a cell of origin that has not yet rearranged or is capable of continuing to rearrange and mutate its immunoglobulin genes. Background Fluorescence in situ hybridization and immunoglobulin (Ig) heavy-chain variable-region (IgHV) mutational status are used to predict outcome in chronic lymphocytic leukemia (CLL). Although DNA aberrations change over time, IgHV sequences and mutational status are considered stable. Patients and Methods In a retrospective review, 409 CLL patients, between 2008 and 2015, had IgHV analysis: 56 patients had multiple analyses performed. Seven patients' IgHV results changed: 2 from unmutated to mutated and 5 from mutated to unmutated IgHV sequence. Results Three concurrently changed their variable heavy-chain sequence. Secondary to allelic exclusion, 2 of the new variable heavy chains produced were biologically nonplausible. Conclusion The existence of these new nonplausible heavy-chain variable regions suggests either the CLL cancer stem-cell maintains the ability to rearrange a previously silenced IgH allele or more likely that the cancer stem-cell produced at least 2 subclones, suggesting that the CLL cancer stem cell exists before the process of allelic exclusion occurs.