Abstract
Chronic myeloid leukemia stem cells (CML LSCs) are a rare and quiescent population that are resistant to tyrosine kinase inhibitors (TKI). When TKI therapy is discontinued in CML patients in deep, sustained and apparently stable molecular remission, these cells in approximately half of the cases restart to grow, resuming the leukemic process. The elimination of these TKI resistant leukemic stem cells is therefore an essential step in increasing the percentage of those patients who can reach a successful long-term treatment free remission (TFR). The understanding of the biology of the LSCs and the identification of the differences, phenotypic and/or metabolic, that could eventually allow them to be distinguished from the normal hematopoietic stem cells (HSCs) are therefore important steps in designing strategies to target LSCs in a rather selective way, sparing the normal counterparts.
Highlights
Accepted: 6 December 2021The development of different generations of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has led the overall survival (OS) of chronic myeloid leukemia (CML) patients to become almost similar to that of a control population without leukemia
It was seen that the combination of Imatinib + INFγ is able to decrease the phosphorylation of STAT5, but it increases the phosphorylation of STAT1, an up-regulator of the survival hint induced by BCL6, clearly delineating another potential pitfall of imatinib and of TKI therapy in general [22]
This has been ascribed to the presence of leukemic stem cells (LSCs) resistant to TKI therapy because of the BCR-ABL1 independent mechanisms of resistance, that can persist even in patients in deep molecular response (DMR) and that, on discontinuation of the TKI therapy, can resume the leukemic process
Summary
The development of different generations of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has led the overall survival (OS) of chronic myeloid leukemia (CML) patients to become almost similar to that of a control population without leukemia. In most of the patients who discontinue the TKI therapy, a regrowth of the leukemic clone and a molecular recurrence of the disease can be observed and only approximately half of those who are achieving a very deep molecular response and approximately only 15–20% of the entire CML population, can definitely and successfully suspend the therapy [1]. This is due to the persistence of leukemic stem cells that are able to survive in spite of the TKI therapy and may have the clonogenic capacity to resume the leukemic process once the TKI therapy has been interrupted. We focus on the peculiar features of CML leukemic stem cells (CML LSCs) that have been so far discovered and that could be potentially useful as targets in designing therapeutic strategies aiming to eliminate in a rather selective way the residual LSCs while sparing their normal counterparts
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