Study into the disruption of the mechanisms responsible for telomere stability in chronic myeloid leukemia - the importance of the role of POT1 and RAP1 in genomic instability in leukemic stem cells

Chronic myeloid leukemia (CML) is a model neoplastic disease; research into this disease has resulted in breakthrough discoveries and led to the development of targeted therapy in oncology; for the first time in this disease, a genetic change was associated with a neoplastic process, and for the first time in this cancer, success was achieved with the use of targeted therapy with tyrosine kinase inhibitors (TKI). Unfortunately, a significant proportion of patients develop resistance to such therapy; another problem is the lack of complete cure due to their insensitivity to the therapy of leukemic stem cells. CML begins with hematopoietic stem cells, which, after a genetic change - the formation of the Philadelphia chromosome as a result of a balanced translocation between chromosomes 9 and 22 - t (9; 22) (q34; q11) and neoplastic transformation, transform into leukemic stem cells. Leukemic stem cells represent one of the most important obstacles to curing chronic myeloid leukemia. Since they are insensitive to tyrosine kinase inhibitors (TKIs), therapy with imatinib or next-generation inhibitors, unfortunately, does not eliminate these cells. In disease evolution, leukemic stem cells show genetic instability and acquire secondary genetic changes. These may be macro-scale phenomena at the level of the cell's genome, such as additional translocations or deletions of chromosomal fragments, they may be micro-changes, such as point mutations, which may, however, have equally serious consequences - e.g. acquisition of resistance to tyrosine kinase inhibitors. Interestingly, these chromosomal changes are often accompanied by a strong shortening of telomeres. Telomeres as nucleoprotein structures located at the ends of eukaryotic chromosomes are one of the key elements responsible for maintaining genomic stability. The importance of this discovery, in particular with regard to the understanding of the fundamental mechanisms of the functioning of organisms at the cellular level, as well as the relationship of telomere disorders with cancer or the aging process, was recognized with the 2009 Nobel Prize in Physiology and Medicine for E. Blackburn, C. Greider and J. Szostak for the discovery "how chromosomes are protected by telomeres and the enzyme telomerase". The discovery of the possibility of elongation of telomere via an alternative pathway based on the mechanisms of recombination, or finding the lack of expression or activity of telomerase in neoplastic cells, indicates, much more than previously thought, the complexity of the mechanisms controlling the telomeric complex. Understanding these molecular mechanisms is therefore important not only for the very fact of understanding the causes of massive chromosomal damage, but also for the use of telomere changes for diagnostic or prognostic purposes. The existing studies as well as our own preliminary results clearly indicate a strong relationship of this process with changes taking place within telomeres. In a preliminary analysis of leukemia cells from patients in different phases of the CSF, we observed differences in telomere length with no or very low expression of TERC and TERT genes (telomerase subunits), and differences in the expression levels of some of the shell-associated proteins (telomere associated). Thus, the obtained preliminary results allowed for the formulation of a hypothesis concerning the active role of the telomeric complex in drug resistance and disease progression. A detailed understanding of the mechanisms responsible for the increasing genomic instability of chronic myeloid leukemia cells, especially leukemic stem cells, which increases with disease progression, could help in the treatment of patients with disease progression. It could also contribute to our understanding of the role of telomeres and the telomere complex in cancer.