scholarly journals Therapy of chronic myeloid leukaemia can benefit from the activation of stem cells: simulation studies of different treatment combinations

2012 ◽  
Vol 106 (11) ◽  
pp. 1742-1752 ◽  
Author(s):  
I Glauche ◽  
K Horn ◽  
M Horn ◽  
L Thielecke ◽  
M AG Essers ◽  
...  
Keyword(s):  
Stem Cells ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Simulation Studies

scholarly journals PO-145 ERK5 pathway inhibitors inhibit the maintenance of chronic myeloid leukaemia stem cells

2018 ◽  
Author(s):  
E Rovida ◽  
I Tusa ◽  
G Cheloni ◽  
A Gozzini ◽  
X Deng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia

scholarly journals Stem cells in chronic myeloid leukaemia

2007 ◽  
Vol 3 (4-5) ◽  
pp. 183-191 ◽  
Author(s):  
Francesca Pellicano ◽  
Tessa L. Holyoake
Keyword(s):  
Stem Cells ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia

BMS-214662 Targets Quiescent Chronic Myeloid Leukaemia Stem Cells and Enhances the Activity of Both Imatinib and Dasatinib (BMS-354825).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 693-693 ◽  
Author(s):  
Mhairi Copland ◽  
Ashley Hamilton ◽  
Elaine K. Allan ◽  
Valerie Brunton ◽  
Tessa L. Holyoake
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Caspase 3 ◽  
Kinase Activity ◽  
Drug Control ◽  
Abl Kinase ◽  
Viable Cells

Abstract Chronic myeloid leukaemia (CML) is a clonal disease of stem cell origin associated with expression of the Philadelphia chromosome and its oncogenic fusion protein product Bcr-Abl. Despite an impressive rate of complete cytogenetic response in chronic phase CML, the majority of patients treated with imatinib mesylate (IM) show persistent molecular disease. Recent work by our group shows that this molecular persistence results from a population of quiescent CML stem cells which are not effectively targeted by IM, the novel, oral, multi-targeted kinase inhibitor dasatinib (BMS-354825; which targets Bcr-Abl and Src kinases), or several rationally designed drug combinations1. Further in vitro studies by our group have demonstrated that the only combination to have an improved response in the quiescent stem cell sub-population was IM with the farnesyl transferase inhibitor (FTI) lonafarnib. BMS-214662 is an atypical non-peptidomimetic cytotoxic FTI, which has been shown to preferentially kill non-dividing cells2 and has anti-leukaemic activity in acute myeloid leukaemia. We assessed the efficacy of this compound alone and in combination with IM and dasatinib in primary CD34+ CML cells in vitro using a CFSE-based flow cytometry method to track cell division, caspase-3 activity to measure apoptosis and dephosphorylation of Crkl to determine Bcr-Abl kinase activity. Primary CD34+ CML cells were cultured for 6 days in serum free medium supplemented with 5 growth factors (IL-3, IL-6, Flt-3 ligand, G-CSF and SCF). Conditions studied were: (1) no drug control, (2) IM (5μM; ~IC90 dose), (3) dasatinib (150nM; ~IC90 dose) (4) BMS-214662 (250nM; ~IC50 dose), (5) IM plus BMS-214662, (6) dasatinib plus BMS-214662. After 6 days culture, there was a significant reduction in total viable cells in all treatment arms relative to the no drug control (P=0.001). The combinations of IM plus BMS-214662 and dasatinib plus BMS-214662 showed increased cytotoxic effect over either IM or dasatinib alone (P=0.024 and P=0.034, respectively). While the IM and dasatinib arms showed significant accumulation of undivided CFSEmax CD34+ CML cells over the no drug control (P=0.04 and P=0.023, respectively), the arms containing BMS-214662 either alone or in combination showed a reduction in these primitive cells to <50% of the no drug control. This reduction was highly statistically significant when either IM or dasatinib alone was compared to the combination with BMS-214662 (P=0.01 and P=0.043, respectively). There were no significant differences in undivided CFSEmax CD34+ CML cells between the BMS-214662 containing arms. At 72 hours, caspase-3 activity was increased in the BMS-214662-containing arms with increased apoptosis in the undivided CFSEmax CD34+ CML cells. BMS-214662 induced dephosphorylation of Crkl in remaining viable cells at 72 hours and 6 days, suggesting inhibition of Bcr-Abl kinase activity. In conclusion, BMS-214662 is highly effective against CML cells, including, for the first time, the primitive quiescent stem cell fraction, overcoming the accumulation of this population seen with IM or dasatinib in vitro.

scholarly journals Strategies For Targeting Chronic Myeloid Leukaemia Stem Cells

2019 ◽  
Vol Volume 9 ◽  
pp. 45-52
Author(s):  
Giovanna Carrà ◽  
Antonio Cartellà ◽  
Beatrice Maffeo ◽  
Alessandro Morotti
Keyword(s):  
Stem Cells ◽  
Chronic Myeloid Leukaemia ◽  
Myeloid Leukaemia

Characterization of cancer stem cells in chronic myeloid leukaemia

2007 ◽  
Vol 35 (5) ◽  
pp. 1347-1351 ◽  
Author(s):  
H.G. Jørgensen ◽  
T.L. Holyoake
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Chronic Myeloid Leukaemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukaemia ◽  
Cell Population ◽  
Single Agent ◽  
Stem Cell Population ◽  
Wild Type ◽  
Apoptosis Protein

CML (chronic myeloid leukaemia) is a myeloproliferative disease that originates in an HSC (haemopoietic stem cell) as a result of the t(9;22) translocation, giving rise to the Ph (Philadelphia chromosome) and bcr-abl oncoprotein. The disease starts in CP (chronic phase), but as a result of genomic instability, it progresses over time to accelerated phase and then to BC (blast crisis), becoming increasingly resistant to therapy. bcr-abl is a constitutively active tyrosine kinase that has been targeted by TKIs (tyrosine kinase inhibitors), including IM (imatinib mesylate), nilotinib and dasatinib. We have developed various flow cytometry techniques to enable us to isolate candidate CML stem cells from CP patients at diagnosis that efflux Hoechst dye, express CD34, lack CD38 and are cytokine-non-responsive in culture over periods of up to 12 days in growth factors. These stem cells have been shown to regenerate bcr-abl-positive haemopoiesis in immunocompromised mice upon transplantation. We previously demonstrated that IM was antiproliferative for CML stem cells but did not induce apoptosis. Clinical experience now confirms that IM may not target CML stem cells in vivo with few patients achieving complete molecular remission and relapse occurring rapidly upon drug withdrawal. Our recent efforts have focused on understanding why CML stem cells are resistant to IM and on trying to find novel ways to induce apoptosis of this population. We have shown that CML stem cells express very high levels of functional wild-type bcr-abl; no kinase domain mutations have been detected in the stem cell population. Dasatinib, a more potent multitargeted TKI than IM, inhibits bcr-abl activity more efficiently than IM but still does not induce apoptosis of the stem cell population. Most recently, we have tested a number of novel drug combinations and found that FTIs (farnesyl transferase inhibitors) have activity against CML. BMS-214662 is the most effective of these and induces apoptosis of phenotypically and functionally defined CML stem cells in vitro, as a single agent and in combination with IM or dasatinib. The effect against CML stem cells is selective with little effect on normal stem cells. The drug is also effective against BC CML stem cells and equally effective against wild-type and mutant bcr-abl, including the most resistant mutant T315I. In association with apoptosis, there is activation of caspase 8 and caspase 3, inhibition of the MAPK pathway, IAP-1 (inhibitor of apoptosis protein-1), NF-κB (nuclear factor κB) and iNOS (inducible nitric oxide synthase). Furthermore, BMS-214662 synergizes with MEK1/2 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 1/2] inhibitors, suggesting a second mechanism other that RAS inhibition for induction of apoptosis. Our intentions are now to explore the activity of BMS-214662 in other cancer stem cell disorders and to move this preclinical work to a clinical trial combining dasatinib with BMS-214662 in CML.

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