CDKIs p18^INK4cand p57^Kip2are involved in quiescence of CML leukemic stem cells after treatment with TKI

Abstract

Chronic Myeloid Leukemia (CML) is sustained by a small population of cells with stem cell characteristics known as Leukemic Stem Cells that are positive to BCR-ABL fusion protein, involved with several abnormalities in cell proliferation, expansion, apoptosis and cell cycle regulation. Current treatment options for CML involve the use of Tirosine Kinase Inhibitor (Imatinib, Nilotinib and Dasatinib), that efficiently reduce proliferation proliferative cells but do not kill non proliferating CML primitive cells that remain and contributes to the persistence of the disease.In order to understand the role of Cyclin Dependent Kinase Inhibitors in CML LSC permanence after TKI treatment, in this study we analyzed cell cycle status, the levels of several CDKIs and the subcellular localization of such molecules in different CML cell lines, as well as primary CD34+CD38−lin− LSC and HSC.Our results demonstrate that cellular location of p18INK4c and p57Kip2 seems to be implicated in the antiproliferative activity of Imatinib and Dasatinib in CML cells and also suggest that the permanence of quiescent stem cells after TKI treatment could be associated with a decrease in p18INK4c and p57Kip2 nuclear location. The differences in p18INK4cand p57Kip2activities in CML and normal stem cells suggest a different cell cycle regulation and provide a platform that could be considered in the development of new therapeutic options to eliminate LSC.

Parthenolide and DMAPT induce cell death in primitive CML cells through reactive oxygen species

“…36 TKIs, which directly target the activation of Bcr-Abl, inhibit proliferation of bulk CML cells; however, a fraction of LSC has been shown to enter quiescence and avoid apoptosis. 15 Here, we found that a fraction of CML cells is able to survive PTL and DMAPT the arrest on cell cycle to be reversed by NAC pre-treatment; however, to our surprise we found that while cells were consistently rescued from cell death with NAC pre-treatment, they readily suffered a cell cycle arrest that could not be explained by ROS induction.…”

“…Although TKI treatments are very effective targeting Bcr‐Abl activation, the quiescent leukaemic pool has been reported as not sensitive to this inhibition 27. Recently, our group reported that the G0/G1 phase fraction increases in CML cells after being treated with TKIs, and that this is dependent on nuclear localization of CDK inhibitors p21 and p18 15. NF‐κB has also been reported as a regulator of cell cycle, and it is therefore relevant to all new therapeutic strategies.…”

“…27 Recently, our group reported that the G0/G1 phase fraction increases in CML cells after being treated with TKIs, and that this is dependent on nuclear localization of CDK inhibitors p21 and p18. 15 NF-κB has also been reported as a regulator of cell cycle, and it is therefore relevant to all new therapeutic strategies. A first approach to analyse this was to verify the effects of PTL and DMAPT on cell proliferation.…”

Exploring receptor tyrosine kinases-inhibitors in Cancer treatments

“…Quiescent cancer cells complicate diagnosis, target therapeutic drugs (TKIs) interventions, chemotherapy and are generally difficult to tackle. The current treatment regimen that involves the use of tyrosine Kinase Inhibitors for rapidly dividing cells do not kill quiescent cells that contribute to cancer relapse [121].…”

Global gene expression profiles of hematopoietic stem and progenitor cells from patients with chronic myeloid leukemia: the effect of in vitro culture with or without imatinib

“…Indeed, both normal and CML hematopoietic stem cells (HSCs) are comprised within a cell population expressing the CD34 antigen, and lacking the expression of CD38 and any lineage‐specific antigen; so that they are referred to as lineage‐negative (Lin − ) cells. The vast majority of normal and leukemic HSCs are quiescent, thus, leukemic HSCs (leukemic stem cells or LSCs) are insensitive to most chemotherapeutic agents, including tyrosine kinase inhibitors, such as IM . Furthermore, both normal HSCs and LSCs reside in specific niches within the bone marrow; such niches play important roles in stem cell function and recent evidence suggests that they contribute to leukemic cell resistance to drugs by protecting them from the action of antineoplastic agents .…”