Combined Effects of As4S4 and Imatinib on Chronic Myeloid Leukemia Cells and BCR-ABL Oncoprotein.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4651-4651
Author(s):  
Tong Yin ◽  
Ying-Li Wu ◽  
Hui-Ping Sun ◽  
Guan-Lin Sun ◽  
Ji Zhang ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Synergistic Effect ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Activity ◽  
Synergistic Effects ◽  
Chronic Phase ◽  
K562 Cells ◽  
G1 Arrest ◽  
Tyrosine Kinase Activity

Abstract Imatinib is a tailored drug for chronic myeloid leukemia (CML), which has very good effects on patients at chronic phase (CP), but not on those at accelerated phase or blast phase. In addition, even among patients at CP, Imatinib seems unable to eradicate the malignant progenitors and a significant portion of patients develops drug resistance after long time use. Arsenic compounds were known as ancient remedies for CML with certain efficacy. The aim of this study was to investigate the potential benefit of combination therapy with Imatinib and arsenic sulfide (As4S4) on BCR-ABL+ K562 cells and fresh CD34+ hematopoietic progenitor cells isolated from CML patients and non-leukemic donors. Analysis of cell proliferation and clonogenic ability showed that As4S4 and Imatinib exerted synergistic effects on both K562 cells and fresh CML cells. The effective concentrations on fresh CML cells were pharmacokinetically available in vivo but had much less inhibitory effect on CD34+ cells from the non-leukemia donors. The synergistic effect of Imatinib/As4S4 combination in terms of anti-proliferation might be connected with their distinct but complementary roles in interfering with the cell cycle progression. Our data showed that Imatinib induced G1 arrest of K562 cells, while As4S4 induced G2/M arrest. In addition, Imatinib induces significant down-regulation of phosphorylated Rb and CDK1, which is in agreement with the G1/S but not G2/M arrest under this drug. However, As4S4 shows no obvious effect on these proteins in spite of a visible effect on G2/M block. Using a number of parameters such as morphology, Annexin V/PI, mitochondrial transmembrane potential, caspase3 activity and Fas/Fas-L, the synergistic effects were revealed on induction of cell apoptosis, largely through mitochondrial pathway. What’s more, the two drugs also exhibited synergistic effect in targeting BCR-ABL protein. While As4S4 triggered its degradation and Imatinib inhibited its tyrosine kinase activity, combined use of the two led to lower protein/enzymatic activity levels of BCR-ABL. In conclusion, our study suggests As4S4 and Imatinib have synergistic effects in inhibiting proliferation, inducing apoptosis of cells and reduction the tyrosine kinase activity of BCR-ABL. Our in vitro data thus strongly suggest a potential clinical application of Imatinib/As4S4 combination on CML.

scholarly journals The P190, P210, and P230 Forms of the BCR/ABL Oncogene Induce a Similar Chronic Myeloid Leukemia–like Syndrome in Mice but Have Different Lymphoid Leukemogenic Activity

1999 ◽  
Vol 189 (9) ◽  
pp. 1399-1412 ◽  
Author(s):  
Shaoguang Li ◽  
Robert L. Ilaria ◽  
Ryan P. Million ◽  
George Q. Daley ◽  
Richard A. Van Etten
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Target Cell ◽  
Myeloid Leukemia ◽  
Kinase Activity ◽  
Philadelphia Chromosome ◽  
Lymphoid Cells ◽  
Tyrosine Kinase Activity ◽  
Lymphoid Leukemia ◽  
B Lymphoid

The product of the Philadelphia chromosome (Ph) translocation, the BCR/ABL oncogene, exists in three principal forms (P190, P210, and P230 BCR/ABL) that are found in distinct forms of Ph-positive leukemia, suggesting the three proteins have different leukemogenic activity. We have directly compared the tyrosine kinase activity, in vitro transformation properties, and in vivo leukemogenic activity of the P190, P210, and P230 forms of BCR/ABL. P230 exhibited lower intrinsic tyrosine kinase activity than P210 and P190. Although all three oncogenes transformed both myeloid (32D cl3) and lymphoid (Ba/F3) interleukin (IL)-3–dependent cell lines to become independent of IL-3 for survival and growth, their ability to stimulate proliferation of Ba/F3 lymphoid cells differed and correlated directly with tyrosine kinase activity. In a murine bone marrow transduction/transplantation model, the three forms of BCR/ABL were equally potent in the induction of a chronic myeloid leukemia (CML)–like myeloproliferative syndrome in recipient mice when 5-fluorouracil (5-FU)–treated donors were used. Analysis of proviral integration showed the CML-like disease to be polyclonal and to involve multiple myeloid and B lymphoid lineages, implicating a primitive multipotential target cell. Secondary transplantation revealed that only certain minor clones gave rise to day 12 spleen colonies and induced disease in secondary recipients, suggesting heterogeneity among the target cell population. In contrast, when marrow from non– 5-FU–treated donors was used, a mixture of CML-like disease, B lymphoid acute leukemia, and macrophage tumors was observed in recipients. P190 BCR/ABL induced lymphoid leukemia with shorter latency than P210 or P230. The lymphoid leukemias and macrophage tumors had provirus integration patterns that were oligo- or monoclonal and limited to the tumor cells, suggesting a lineage-restricted target cell with a requirement for additional events in addition to BCR/ABL transduction for full malignant transformation. These results do not support the hypothesis that P230 BCR/ABL induces a distinct and less aggressive form of CML in humans, and suggest that the rarity of P190 BCR/ABL in human CML may reflect infrequent BCR intron 1 breakpoints during the genesis of the Ph chromosome in stem cells, rather than intrinsic differences in myeloid leukemogenicity between P190 and P210.

scholarly journals Chronic myeloid leukemia in children and adolescents (A bout 2 cases)

2021 ◽  
Author(s):  
meryeme abddaoui ◽  
ahmed faleh ◽  
imane tlemçani ◽  
sara ben miloud ◽  
moncef amrani hassani
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Children And Adolescents ◽  
Myeloid Leukemia ◽  
Kinase Activity ◽  
Fusion Gene ◽  
Rare Entity ◽  
Tyrosine Kinase Activity ◽  
Leukemia In Children

Pediatric chronic myeloid leukemia is a rare entity (2-5% of childhood leukemias) classified as a myeloproliferative neoplasia characterized by the presence of the BCR-ABL fusion gene, the oncogenic translocation product (9; 22) responsible for the disease through its deregulated tyrosine kinase activity.

scholarly journals Intracellular delivery of anti-BCR/ABL antibody by PLGA nanoparticles suppresses the oncogenesis of chronic myeloid leukemia cells

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Guoyun Jiang ◽  
Zhenglan Huang ◽  
Ying Yuan ◽  
Kun Tao ◽  
Wenli Feng
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Intracellular Delivery ◽  
Tyrosine Kinase Activity

Abstract Background The pathogenesis of chronic myeloid leukemia (CML) is the formation of the BCR/ABL protein, which is encoded by the bcr/abl fusion gene, possessing abnormal tyrosine kinase activity. Despite the wide application of tyrosine kinase inhibitors (TKIs) in CML treatment, TKIs drug resistance or intolerance limits their further usage in a subset of patients. Furthermore, TKIs inhibit the tyrosine kinase activity of the BCR/ABL oncoprotein while failing to eliminate the pathologenic oncoprotein. To develop alternative strategies for CML treatment using therapeutic antibodies, and to address the issue that antibodies cannot pass through cell membranes, we have established a novel intracellular delivery of anti-BCR/ABL antibodies, which serves as a prerequisite for CML therapy. Methods Anti-BCR/ABL antibodies were encapsulated in poly(d, l-lactide-co-glycolide) nanoparticles (PLGA NPs) by a double emulsion method, and transferrin was labeled on the surface of the nanoparticles (Ab@Tf-Cou6-PLGA NPs). The characteristics of nanoparticles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Cellular uptake of nanoparticles was measured by flow cytometry (FCM). The effect of nanoparticles on the apoptosis and proliferation of CML cells was testified by FCM and CCK-8 assay. In addition, the anti-cancer impact of nanoparticles was evaluated in mouse models of CML. Results The results demonstrated that the Ab@Tf-Cou6-PLGA NPs functioned as an intracellular deliverer of antibodies, and exhibited an excellent effect on degrading BCR/ABL oncoprotein in CML cells via the Trim-Away pathway. Treatment with Ab@Tf-Cou6-PLGA NPs inhibited the proliferation and induced the apoptosis of CML cells in vitro as well as impaired the oncogenesis ability of CML cells in vivo. Conclusions In conclusion, our study indicated that this approach achieved safe and efficient intracellular delivery of antibodies and degraded BCR/ABL oncoprotein via the Trim-Away pathway, which provides a promising therapeutic strategy for CML patients, particularly those with TKI resistance.

Phosphorylation of Spleen Tyrosine Kinase (Syk) Appears to Be Related to the Blast Phase of Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4425-4425
Author(s):  
Céline Bourgne ◽  
Alexandre Janel ◽  
Jacques Chassagne ◽  
Chantal Rapatel ◽  
Olivier Tournilhac ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
K562 Cells ◽  
Polymorphonuclear Cells ◽  
Src Kinases ◽  
Blast Phase ◽  
Blast Cells

Abstract Abstract 4425 Introduction: Despite the major benefit of TKI in the treatment of Chronic Myeloid Leukemia (CML) chronic phase, some of patients are resistant or progress to blast phase (BP) becoming not very accessible to therapy. We have been interested in the Syk molecule as a potential marker for CML progression for several reasons: i) its potential interaction with Src kinases, activated by BCR-ABL, and tyrosine kinase receptors, ii) its involvement in the molecular complexes activating actin and the cytoskeleton and integrin signalling pathways, regulating cell adhesion, a property that is impaired in CML, iii) its interaction with the PI3K/Akt pathway, activated by BCR-ABL. Furthermore, resistance to nilotinib was recently showed dependent on Syk expression. Method: The amount of Syk transcript was analyzed in primary cells using the 2-ΔΔ Ct method and was normalized to the endogenous reference gene (β2-microglobuline) and K562 cells as the calibrator. Using flow cytometry, we evaluated the expression of Syk and pSyk348 in K562 cells and in polymorphonuclear cells from 3 healthy donors (HD-PMN), primitive CML cells from 15 patients in chronic phase (CP) (patients #1 to #15) at diagnosis, in the blast cells from 4 patients in accelerated phase (AP) (patient#16, #17, #18 and #19) and from 2 patients in blast crisis (BC) (patient#20, #21). The level of intracellular dasatinib (DAS) was evaluated by an original flow cytometry method (Bourgne et al. Cytometry Part A, in press). Results: We observed a significant over expression of Syk mRNA in BP-CML cells, whereas there is no difference between HD-PMN and CP-CML cells. At the protein level we detected a decrease (2 times; p<0.001) in and a tendency to increase (1.5 times; p=0.5) in the expression of Syk in CP-CML cells and BP-CML cells respectively compared with HD-PMN cells. Interestingly, we did not observe any expression of pSyk348 in HD-PMN or in granulocytic cells from CP-CML (n=15) but we systematically detected pSyk348 expression in the blast cells of the 6 patients (positive/control ratio: 2.3 ± 0.3) in advanced phases of CML. Moreover we did not found Syk phosphorylation in CP cells from one patient resistant to imatinib, then nilotinib and dasatinib but we detected pSyk348 only when his CML progressed, strengthening the hypothesis of a link between Syk phosphorylation and BP of CML. We confirmed in vitro that Dasatinib was able to rapidly (15 min) inhibit Syk phosphorylation in K562 cells and in blast cells from patient #17. Then we could follow dasatinib uptake into target blast cells, and expression of pSyk348 before and 6, 12, 36, 60, 84 and 136 hours after the first dose of DAS. We observed a significant storage of DAS in blast cells reaching a plateau after the 4th dose even though analyses were done 12 hrs after each dose. However, after a slight fall of blood leukocytes and blast cells numbers corresponding to a sharp drop of pSyk348 we observed an increase of blood malignant cells in parallel of a strong recurrence of pSyk348 at H60. Discussion: We observed a constitutive expression of Syk348 only in blast cells from advanced phases of CML, including in one patient we could follow from the TKI resistant phases to blast phase, strongly suggesting that Syk activation could be a pertinent biomarker for CML progression and could represent a potential target for combinatory therapy. The fact that we observed in one patient a correlation between Syk348 expression and malignant cell resistance even though cells stored dasatinib suggests a BCR-ABL/Src kinases independent mechanism of Syk phosphorylation in blast cells. Targeting Syk in BP-CML should offer new therapeutic option to patients with disease progression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Meta-Analysis of Gastrointestinal Adverse Events from Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1643
Author(s):  
Prahathishree Mohanavelu ◽  
Mira Mutnick ◽  
Nidhi Mehra ◽  
Brandon White ◽  
Sparsh Kudrimoti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Chronic Phase ◽  
Molecular Response ◽  
Gastrointestinal Adverse Events

Tyrosine kinase inhibitors (TKIs) are the frontline therapy for BCR-ABL (Ph+) chronic myeloid leukemia (CML). A systematic meta-analysis of 43 peer-reviewed studies with 10,769 CML patients compared the incidence of gastrointestinal adverse events (GI AEs) in a large heterogeneous CML population as a function of TKI type. Incidence and severity of nausea, vomiting, and diarrhea were assessed for imatinib, dasatinib, bosutinib, and nilotinib. Examination of combined TKI average GI AE incidence found diarrhea most prevalent (22.5%), followed by nausea (20.6%), and vomiting (12.9%). Other TKI GI AEs included constipation (9.2%), abdominal pain (7.6%), gastrointestinal hemorrhage (3.5%), and pancreatitis (2.2%). Mean GI AE incidence was significantly different between TKIs (p < 0.001): bosutinib (52.9%), imatinib (24.2%), dasatinib (20.4%), and nilotinib (9.1%). Diarrhea was the most prevalent GI AE with bosutinib (79.2%) and dasatinib (28.1%), whereas nausea was most prevalent with imatinib (33.0%) and nilotinib (13.2%). Incidence of grade 3 or 4 severe GI AEs was ≤3% except severe diarrhea with bosutinib (9.5%). Unsupervised clustering revealed treatment efficacy measured by the complete cytogenetic response, major molecular response, and overall survival is driven most by disease severity, not TKI type. For patients with chronic phase CML without resistance, optimal TKI selection should consider TKI AE profile, comorbidities, and lifestyle.

BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet

Blood ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1208-1215 ◽  
Author(s):  
Simona Soverini ◽  
Andreas Hochhaus ◽  
Franck E. Nicolini ◽  
Franz Gruber ◽  
Thoralf Lange ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Mutation Analysis ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Direct Sequencing ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Abl Kinase

AbstractMutations in the Bcr-Abl kinase domain may cause, or contribute to, resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia patients. Recommendations aimed to rationalize the use of BCR-ABL mutation testing in chronic myeloid leukemia have been compiled by a panel of experts appointed by the European LeukemiaNet (ELN) and European Treatment and Outcome Study and are here reported. Based on a critical review of the literature and, whenever necessary, on panelists' experience, key issues were identified and discussed concerning: (1) when to perform mutation analysis, (2) how to perform it, and (3) how to translate results into clinical practice. In chronic phase patients receiving imatinib first-line, mutation analysis is recommended only in case of failure or suboptimal response according to the ELN criteria. In imatinib-resistant patients receiving an alternative TKI, mutation analysis is recommended in case of hematologic or cytogenetic failure as provisionally defined by the ELN. The recommended methodology is direct sequencing, although it may be preceded by screening with other techniques, such as denaturing-high performance liquid chromatography. In all the cases outlined within this abstract, a positive result is an indication for therapeutic change. Some specific mutations weigh on TKI selection.

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