Telomere lenght and telomerase activity delineate distinctive replicative features of the B/CLL subgroups defined by immunoglobulin V gene mutations

Patients with B-cell chronic lymphocytic leukemia (B-CLL) segregate into sub- groups with very different survival times. Because clinical observations suggest that leukemic cells accumulate at differ- ent rates, we measured telomere length and telomerase activity in B-CLL cells to distinguish differences in cellular replica- tion. Our data indicate that the telomeres of B-CLL cells are shorter than telomeres of B cells from healthy subjects, indicat- ing that the leukemic cells have a pro- longed proliferative history. Leukemic cells of the immunoglobulin V gene muta- tion subgroups differ in telomere length and telomerase activity. B lymphocytes from the subgroup with poor outcome and with limited IgV gene mutations have uniformly shorter telomeres and more telomerase activity than those from the subgroup with better outcome and with considerable mutations. Differences in telomere length appear to largely reflect the proliferative histories of precursors of the leukemic cells, although differences in cell division, masked by the action of telomerase, cannot be excluded. These results may provide insight into the stages of maturation and the activation path- ways of the cells that give rise to B-CLL. In addition, they reinforce the concept that B-CLL is not simply an accumulative disease of slowly dividing B lymphocytes but possibly one of B cells with extensive proliferative histories. (Blood. 2004;103: 375-382).

Patients with B-cell chronic lymphocytic leukemia (B-CLL) segregate into sub-groups with very different survival times. Because clinical observations suggest that leukemic cells accumulate at different rates, we measured telomere length and telomerase activity in B-CLL cells to distinguish differences in cellular replication. Our data indicate that the telomeres of B-CLL cells are shorter than telomeres of B cells from healthy subjects, indicating that the leukemic cells have a prolonged proliferative history. Leukemic cells of the immunoglobulin V gene mutation subgroups differ in telomere length and telomerase activity. B lymphocytes from the subgroup with poor outcome and with limited IgV gene mutations have uniformly shorter telomeres and more telomerase activity than those from the subgroup with better outcome and with considerable mutations. Differences in telomere length appear to largely reflect the proliferative histories of precursors of the leukemic cells, although differences in cell division, masked by the action of telomerase, cannot be excluded. These results may provide insight into the stages of maturation and the activation pathways of the cells that give rise to B-CLL. In addition, they reinforce the concept that B-CLL is not simply an accumulative disease of slowly dividing B lymphocytes but possibly one of B cells with extensive proliferative histories. © 2004 by The American Society of Hematology.