Dynamic length changes of telomeres and their nuclear organization in chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the t(9;22) translocation. As in most cancers, short telomeres are one of the features of CML cells, and telomere shortening accentuates as the disease progresses from the chronic phase to the blastic phase. Although most individual telomeres are short, some of them are lengthened, and long individual telomeres occur non-randomly and might be associated with clonal selection. Telomerase is the main mechanism used to maintain telomere lengths, and its activity increases when CML evolves toward advanced stages. ALT might be another mechanism employed by CML cells to sustain the homeostasis of their telomere lengths and this mechanism seems predominant at the early stage of leukemogenesis. Also, telomerase and ALT might jointly act to maintain telomere lengths at the chronic phase, and as CML progresses, telomerase becomes the major mechanism. Finally, CML cells display an altered nuclear organization of their telomeres which is characterized by the presence of high number of telomeric aggregates, a feature of genomic instability, and differential positioning of telomeres. CML represents a good model to study mechanisms responsible for dynamic changes of individual telomere lengths and the remodeling of telomeric nuclear organization throughout cancer progression.

Figure 1

A Suggested model for telomere length maintenance during a course of CML progression. At the initiation of CML, leukemic cells use exclusively alternative lengthening of telomere (ALT) to maintain their telomeres. As CML progresses from an early to a late stage of the chronic phase, clones expressing telomerase become predominant. At the accelerated and blastic phases, the quasi totality of the cells expresses telomerase, but few ALT positive clones remain. At the blastic phase, clones expressing high activity of telomerase appear and become resistant to imatinib. Blue circles: Cells using ALT; Red circles: cells using telomerase; Brown circles: Cells expressing high telomerase activity and resistant to imatinib.