scholarly journals Combined inhibition of β-catenin and Bcr–Abl synergistically targets tyrosine kinase inhibitor-resistant blast crisis chronic myeloid leukemia blasts and progenitors in vitro and in vivo

Leukemia ◽  
2017 ◽  
Vol 31 (10) ◽  
pp. 2065-2074 ◽  
Author(s):  
H Zhou ◽  
P Y Mak ◽  
H Mu ◽  
D H Mak ◽  
Z Zeng ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Blast Crisis

BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2843-2853 ◽  
Author(s):  
Mhairi Copland ◽  
Francesca Pellicano ◽  
Linda Richmond ◽  
Elaine K. Allan ◽  
Ashley Hamilton ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Hematopoietic Stem

Chronic myeloid leukemia (CML), a hematopoietic stem-cell disorder, cannot be eradicated by conventional chemotherapy or the tyrosine kinase inhibitor imatinib mesylate (IM). To target CML stem/progenitor cells, we investigated BMS-214662, a cytotoxic farnesyltransferase inhibitor, previously reported to kill nonproliferating tumor cells. IM or dasatinib alone reversibly arrested proliferation of CML stem/progenitor cells without inducing apoptosis. In contrast, BMS-214662, alone or in combination with IM or dasatinib, potently induced apoptosis of both proliferating and quiescent CML stem/progenitor cells with less than 1% recovery of Philadelphia-positive long-term culture-initiating cells. Normal stem/progenitor cells were relatively spared by BMS-214662, suggesting selectivity for leukemic stem/progenitor cells. The ability to induce selective apoptosis of leukemic stem/progenitor cells was unique to BMS-214662 and not seen with a structurally similar agent BMS-225975. BMS-214662 was cytotoxic against CML blast crisis stem/progenitor cells, particularly in combination with a tyrosine kinase inhibitor and equally effective in cell lines harboring wild-type vs mutant BCR-ABL, including the T315I mutation. This is the first report of an agent with activity in resistant and blast crisis CML that selectively kills CML stem/progenitor cells through apoptosis and offers potential for eradication of chronic phase CML.

scholarly journals SNP array analysis of tyrosine kinase inhibitor-resistant chronic myeloid leukemia identifies heterogeneous secondary genomic alterations

Blood ◽  
2010 ◽  
Vol 115 (5) ◽  
pp. 1049-1053 ◽  
Author(s):  
Daniel Nowak ◽  
Seishi Ogawa ◽  
Markus Müschen ◽  
Motohiro Kato ◽  
Norihiko Kawamata ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Genomic Alterations ◽  
Tki Resistance

AbstractTo elucidate whether tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia is associated with characteristic genomic alterations, we analyzed DNA samples from 45 TKI-resistant chronic myeloid leukemia patients with 250K single nucleotide polymorphism arrays. From 20 patients, matched serial samples of pretreatment and TKI resistance time points were available. Eleven of the 45 TKI-resistant patients had mutations of BCR-ABL1, including 2 T315I mutations. Besides known TKI resistance-associated genomic lesions, such as duplication of the BCR-ABL1 gene (n = 8) and trisomy 8 (n = 3), recurrent submicroscopic alterations, including acquired uniparental disomy, were detectable on chromosomes 1, 8, 9, 17, 19, and 22. On chromosome 22, newly acquired and recurrent deletions of the IGLC1 locus were detected in 3 patients, who had previously presented with lymphoid or myeloid blast crisis. This may support a hypothesis of TKI-induced selection of subclones differentiating into immature B-cell progenitors as a mechanism of disease progression and evasion of TKI sensitivity.

scholarly journals Features of the etythropoesis upon treatment of chronic myeloid leukemia with tyrosine kinase inhibitor

2014 ◽  
Vol 68 (3) ◽  
pp. 51-54
Author(s):  
I. Sviezhentseva ◽  
D. Bilko ◽  
N. Bilko ◽  
I. Dyagil
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukemia ◽  
Culture Medium ◽  
Cultured Cells ◽  
Kinase Inhibitor ◽  
Choice Of Treatment ◽  
First And Second Generation

A functional activity of erythroid hematopoietic cells of patients with chronic myeloid leukemia, who were treated with tyrosine kinase inhibitor of the first and second generation was investigated. Samples of bone marrow of patients with resistance to tyrosine kinase inhibitor treatment show an increase of erythroid colonies number provided that there is erythropoietin in the culture medium. Furthermore, it was found that clone cells in culture in vitro acquire the ability to differentiate towards erythroid direction in the absence of a culture medium culturing exogenous erythropoietin when they have a resistance to imatinib and nilotinib. Thus, the determination of proliferative activity of erythroid hematopoiesis level in cultured cells in vitro may serve as an important prognostic factor for the further choice of treatment strategy.

Treatment of Chronic Myeloid Leukemia Elderly Patients in the Tyrosine Kinase Inhibitor Era

2013 ◽  
Vol 13 (7) ◽  
pp. 755-767 ◽  
Author(s):  
Domenico Russo ◽  
Michele Malagola ◽  
Cristina Skert ◽  
Carla Filì ◽  
Cesare Bergonzi ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Elderly Patients ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor

scholarly journals Thrombotic microangiopathy in dasatinib-treated patients with chronic myeloid leukemia

2019 ◽  
Vol 4 (1-2) ◽  
pp. 41-45 ◽  
Author(s):  
Takeo Koshida ◽  
Sylvia Wu ◽  
Hitoshi Suzuki ◽  
Rimda Wanchoo ◽  
Vanesa Bijol ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Thrombotic Microangiopathy ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kidney Biopsy ◽  
Kinase Inhibitor ◽  
Target Effect

Dasatinib is the second-generation tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia. Proteinuria has been reported with this agent. We describe two kidney biopsy–proven cases of dasatinib-induced thrombotic microangiopathy that responded to stoppage of dasatinib and using an alternate tyrosine kinase inhibitor. Certain specific tyrosine kinase inhibitors lead to endothelial injury and renal-limited thrombotic microangiopathy. Hematologists and nephrologists need to be familiar with this off-target effect of dasatinib.

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