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Imatinib and Nilotinib induced molecular changes in Philadelphia chromosome-positive Chronic Myelogenous Leukemia

ABSTRACT: Chronic myelogenous leukemia (CML) is a malignant stem cell disease characterized by a reciprocal translocation between chromosome 9 and 22. The selective bcr-abl tyrosine-kinase inhibitor Imatinib has become the therapy of choice for patients with newly diagnosed CML including those previously considered candidates for allogeneic haematopoietic stem cell transplantation. The tyrosine-kinase inhibitor Nilotinib is a derivate of Imatinib with higher potency. To examine the molecular and functional effects of Nilotinib and Imatinib in chronic myelogenous leukemia, we performed gene expression and functional analyses in K562 cells following treatment with the two tyrosine kinase inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE19567 | GEO | 2009/12/19

SECONDARY ACCESSION(S): PRJNA122473

REPOSITORIES: GEO

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Transcription profiling of human K562 cells reveals Imatinib and Nilotinib induced molecular changes in Philadelphia chromosome-positive Chronic Myelogenous Leukemia

Project description:Chronic myelogenous leukemia (CML) is a malignant stem cell disease characterized by a reciprocal translocation between chromosome 9 and 22. The selective bcr-abl tyrosine-kinase inhibitor Imatinib has become the therapy of choice for patients with newly diagnosed CML including those previously considered candidates for allogeneic haematopoietic stem cell transplantation. The tyrosine-kinase inhibitor Nilotinib is a derivate of Imatinib with higher potency. To examine the molecular and functional effects of Nilotinib and Imatinib in chronic myelogenous leukemia, we performed gene expression and functional analyses in K562 cells following treatment with the two tyrosine kinase inhibitors. Experiment Overall Design: Affymetrix U133A 2.0 microarrays were used to examine the gene expression profile of K562 cells after in vitro treatment with Imatinib (0.5 ÂµM) or Nilotinib (0.05 ÂµM) for 24 hours. Gene expression data of the treated cells were compared with data of untreated cells.

2010-01-19 | E-GEOD-19567 | biostudies-arrayexpress

Transcription profiling of human CML cell line resistant to cyclophosphamide using oligonucleotide arrays and response to TKI

Project description:Acquired imatinib resistance in chronic myelogenous leukemia (CML) can be the consequence of mutations in the kinase domain of BCR-ABL or increased protein levels. However, as in other malignancies, acquired resistance to cytostatic drugs is a common reason for treatment failure or disease progression. As a model for drug resistance, we developed a CML cell line resistant to cyclophosphamide (CP). Using oligonucleotide arrays, we examined changes in global gene expression. Selected genes were also examined by real-time PCR and flow cytometry. Neither the parent nor the resistant lines had mutations in their ATP binding domain. Filtering genes with a low-base line expression, a total of 239 genes showed significant changes (162 up- and 77 down-regulated) in the resistant clone. Most of the up-regulated genes were associated with metabolism, signal transduction, or encoded enzymes. The gene for aldehyde dehydrogenase 1 was over-expressed more than 2000 fold in the resistant clone. BCR-ABL was expressed in both cell lines to a comparable extent. When exposed to the tyrosine kinase inhibitors imatinib and nilotinib, both lines were sensitive. In conclusion, we found multiple genetic changes in a CML cell line resistant to CP related to metabolism, signal transduction or apoptosis. Despite these changes, the resistant cells retained sensitivity to tyrosine kinase inhibitors. Experiment Overall Design: A CML cell line and a CP resistant subline were compared by gene array. In addition other markers, the expression of BCR-ABL and the sensitivity to tyrosine kinase inhibitors were tested.

2009-04-25 | E-GEOD-7114 | biostudies-arrayexpress

Inhibition of ABL1 tyrosine kinase reduces HTLV-1 in peripheral blood mononuclear cells from HTLV-1-associated myelopathy/tropical spastic paraparesis patients

Project description:Human T-cell leukemia virus type 1 (HTLV-1) causes incurable adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have increased levels of HTLV-1-infected cells compared with asymptomatic HTLV-1 carriers. However, the roles played by cellular genes in HTLV-1-infected CD4+ T cells await discovery. We combined microarray data and pathway analysis, and found that the ABL1 tyrosine kinase gene is a critical gene in HAM/TSP. ABL1 is a known survival factor for T- and B-lymphocytes. ABL1 is also part of the fused gene (BCR-ABL) known to be responsible for chronic myelogenous leukemia (CML), and tyrosine kinase inhibitors (TKI), including imatinib, nilotinib, and dasatinib, are in safe clinical use for treating CML. To evaluate whether ABL1 is indeed critical for the pathogenesis of HAM/TSP, we investigated the effect of ABL1 inhibitors on HTLV-1-infected cells. We developed a propidium monoazide-HTLV-1 viability quantitative PCR assay, which distinguishes DNA from live cells and DNA from dead cells. Using this method, we were able to measure the HTLV-1 proviral load (PVL) in live cells alone when peripheral blood mononuclear cells (PBMCs) from HAM/TSP cases were treated with TKI. Treating the PBMCs with nilotinib or dasatinib produced significant reductions in the PVL (21.0% and 17.5%, respectively) in live cells. Furthermore, a retrospective survey based on our clinical records found a rare case of HAM/TSP, where the patient also suffered from CML. The patient showed an 84.2% PVL reduction after CML treatment with imatinib. We conclude that inhibiting the ABL1 tyrosine kinase specifically reduced the PVL in PBMCs from patients with HAM/TSP, suggesting that ABL1 is a significant gene for the survival of HTLV-1-infected cells and that TKI may be a potential therapeutic agent for HAM/TSP.

2020-05-26 | GSE132666 | GEO

Comparative analysis of a CML cell line resistant to cyclophosphamide using oligonucleotide arrays and response to TKI

2007-02-24 | GSE7114 | GEO

BCR-ABL1 inhibitors decrease cholesterol and atherosclerosis, and activate coagulation in a translational mouse model

Project description:Objectives: Treatment with the second and third generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) increases cardiovascular risk in chronic myeloid leukemia (CML) patients. We investigated the multifactorial process of TKI-induced vascular adverse effects in a translational model for atherosclerosis, the APOE3*Leiden.CETP mouse. Approach and results: Mice were treated for sixteen weeks with imatinib (150 mg/kg BID), nilotinib (10 and 30 mg/kg QD) or ponatinib (3 and 10 mg/kg QD), giving similar drug exposures as in CML-patients. Cardiovascular risk factors were analyzed throughout the study, and histopathological analysis of atherosclerosis and transcriptome analysis of the liver was performed. Imatinib and ponatinib decreased plasma cholesterol (imatinib, -69%, :<0.001; ponatinib 3mg/kg, -37%, P<0.001; ponatinib 10 mg/kg -44%, P<0.001) and atherosclerotic lesion area (imatinib, -78%, P<0.001; ponatinib 3 mg/kg, -52%, P=0.014; ponatinib 10 mg/kg, -48%, P=0.001), which were not affected by nilotinib. In addition, imatinib increased plaque stability. Gene expression and pathway analysis predicted that ponatinib may lead to a pro-coagulant state by adversely affecting coagulation factors of both the contact activation (intrinsic) and tissue factor (extrinsic) pathways. The coagulation factor VII in plasma was increased by ponatinib, whereas nilotinib increased FVIIa. Conclusion: Imatinib showed a beneficial cardiovascular risk profile, whereas nilotinib and ponatinib increase the cardiovascular risk through induction of a pro-thrombotic state.

2018-05-24 | GSE103908 | GEO

Bulk RNA-seq analysis of primary CML CD34+ cells (n=3) treated with idasanutlin alone or in combination with nilotinib in vitro

Project description:Bulk RNA-seq was performed on primary human CML CD34+ cells to understand the molecular consequences of treatment with the MDM2 inhibitor idasanutlin alone and in combination with the tyrosine kinase inhibitor nilotinib for 24 hrs and 72 hrs.

2023-12-19 | GSE218183 | GEO

Effect of imatinib on philadelphia chromosome positive acute lymphoblastic leukemia

Project description:The Philadelphia chromosome (Ph) encodes the oncogenic BCR-ABL1 tyrosine kinase, which defines a subset of acute lymphoblastic leukemia (ALL) with a particularly unfavorable prognosis. In this study, the tyrosine kinase inhibitor imatinib was used for pharmacological inhibition of BCR-ABL1. Gene expression profiles of Ph+ ALL cell lines were analyzed in response to imatinib treatment.

2010-09-10 | GSE23743 | GEO

Single cell RNA-seq analysis of the effects of idasanutlin and/or nilotinib on primary human CML cells engrafted into the bone marrow of immunocompromised mice

Project description:Single cell RNA-seq was performed on primary human CML cells engrafted into the bone marrow of immunocompromised mice to understand the molecular consequences of treatment with the tyrosine kinase inhibitor nilotinib alone and in combination with the MDM2 inhibitor idasanutlin.

2023-12-19 | GSE218185 | GEO

BCR-ABL triggers a glucose-dependent survival program during leukemogenesis through the suppression of TXNIP

Project description:Imatinib is highly effective in the treatment of chronic myelogenous leukemia (CML), but the primary and acquired imatinib resistance remains the big hurdle. Molecular mechanisms for CML resistance to tyrosine kinase inhibitors, beyond point mutations in BCR-ABL kinase domain, still need to be addressed. Here, we demonstrated that TXNIP is a novel BCR-ABL target gene. Suppression of TXNIP is responsible for BCR-ABL triggered glucose metabolic reprogramming and mitochondrial homeostasis. Mechanistically, Miz-1/P300 complex transactivates TXNIP through the recognition of TXNIP core promoter region, responding to the c-Myc suppression by either imatinib or BCR-ABL knockdown. TXNIP restoration sensitizes CML cells to imatinib treatment and compromises imatinib resistant CML cell survival, predominantly through the blockage of both glycolysis and glucose oxidation which results in the mitochondrial dysfunction and ATP production. In particular, TXNIP suppresses expressions of the key glycolytic enzyme, HK2 and LDHA, potentially through Fbw7-dependent c-Myc degradation. In accordance, BCR-ABL suppression of TXNIP provides a novel survival pathway for the transformation of mouse BM cells. Combination of drug inducing TXNIP expression with imatinib synergistically kills CML cells from patients and further extends the survival of CML mice. Thus, the activation of TXNIP represents an effective strategy for CML treatment to overcome resistance.

2023-05-03 | GSE218451 | GEO

Effect of imatinib on philadelphia chromosome positive acute lymphoblastic leukemia

2010-09-10 | E-GEOD-23743 | biostudies-arrayexpress

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