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The impact of a drug transporter ABCG2 haplotype in molecular response of chronic myelogenous leukemia patients is modulated by imatinib dose

ABSTRACT: We analysed the impact of single nucleotide polymorphisms (SNPs) in drug transporter genes on the molecular response to imatinib, using 857 SNPs covering 94 drug transporter genes on 355 chronic phase chronic myeloid leukemia (CP-CML) patients. Samples were analyzed with respect to sex, imatinib daily dose, SOKAL score and the levels of molecular responses. The 'characteristics: molecular response' values represent the ratio BCR-ABL/ABL*100, which is determined by RT-QPCR (real time quantitative PCR). It is the percentage of the number of copies of BCR-ABL transcript on the number of ABL transcript copies.

ORGANISM(S): Homo sapiens

SUBMITTER: Marc Delord

PROVIDER: E-GEOD-52107 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The impact of a drug transporter ABCG2 haplotype in molecular response of chronic myelogenous leukemia patients is modulated by imatinib dose

Project description:We analysed the impact of single nucleotide polymorphisms (SNPs) in drug transporter genes on the molecular response to imatinib, using 857 SNPs covering 94 drug transporter genes on 355 chronic phase chronic myeloid leukemia (CP-CML) patients.

2014-06-30 | GSE52107 | GEO

Comparative analysis of BCR-ABL tyrosine kinase inhibitors in BCR-ABL positive K562 cells

Project description:Tyrosine kinase activity is the crucial enzymatic activity driving all known functions of the BCR-ABL protein and is required for protection from apoptosis by BCR-ABL, therefore, targeting this enzyme is an effective approach for therapeutic strategies. Recently, a novel structural entity, imatinib (STI571; Novartis, Basel, Switzerland), a potent and selective inhibitor of the tyrosine kinase activity of BCR-ABL, has shown promise against Ph-positive leukemia in human clinical trials. However, the emergence of imatinib resistance in patients with acute forms of Ph-positive leukemia has highlighted the need for overriding chemotherapy to eradicate this disease. AMN107 and BMS-354825 are clinically active “next-generation” BCR-ABL inhibitors. One potentially powerful approach is to use these compounds in combination with imatinib. The rationale for such approaches is that an inhibitor cocktail may target the widest range of resistant clones and thereby delay the onset of acquired drug resistance. More potent BCR-ABL inhibitors would be to target residual leukemia that persists in patients in whom imatinib induces durable remission but failed to eradicate the disease. From these points, our studies are performed to determine (1) the differences of molecular signaling pathways between BMS-354825 and imatinib (2) the mechanisms by which drug resistance of BMS-354825 and imatinib occur except for point mutation of BCR-ABL kinase domain. Keywords: drug sensitivity

2006-03-31 | GSE2810 | 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

Gene expression profile of Baf3 cells conditionally expressing BCR-ABL in presence and absence of Growth factor IL-3

Project description:The Baf3 are dependent on IL-3 for grwoth however transformation by BCR -ABL oncogene causes BAf3 cells independent of IL-3. The BAf3 cells expressing BCR-ABL are dependent on continuous expression of BCR_ABL for growth. Inhibitionof BCR-ABL by its inhibitor Imatinib cause these cells to undergo apoptosis. When these cells are grown with IL-3 these cells do not respond to Imatinib mediated grwoth arrest.

2017-03-20 | GSE75057 | GEO

Imatinib induces mesenchymal stem cell-mediated drug resistance in BCR-ABL–positive acute lymphoblastic leukemia

Project description:One of the main objective of this study is to characterize Imatinib induced MSCs-mediated resistance evolution in BCR-ABL+ ALL. Tyrosine kinase inhibitor (TKI) Imatinib (IM) is used as a frontline therapy for BCR-ABL–positive (BCR-ABL+) acute lymphoblastic leukemia (ALL). However, resistance to IM therapy develops rapidly in a substantial proportion of treated patients, and the molecular mechanisms underlying the resistance are poorly understood. In this study, we identified a novel cascade of consequential events that are initiated by IM, which traverse through mesenchymal stem/stromal cells (MSCs) to leukemic cells, and lead to IM resistance. Our data showed that MSCs exposed to IM were decreased in their stemness and acquired a new functional status that enabled the formation of leukemic cell niches. These MSCs had increased expression of genes encoding chemo-attractants, adhesion molecules, and pro-survival stimulant growth factors. We found that BCR-ABL+ leukemic cells persistently exposed to IM were able to switch from BCR-ABL–driven signaling to growth factor–driven signaling for survival, and this switch was reversible. Blocking both the BCR-ABL–driven pathway and the growth factor–driven JAK pathway effectively eradicated the leukemic cell niches. Our findings illustrate TKI-induced, MSC-mediated drug resistance, suggesting an effective way to eliminate this type of drug resistance in patients with BCR-ABL+ ALL. Gene expression signatures were compared from triplicate samples of MSCs that were either treated with vehicle or imatinib for 32, 64 and 96 hours.

2015-09-01 | E-GEOD-56472 | biostudies-arrayexpress

Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl

Project description:Although Bcr-Abl kinase inhibitors have proven effective in the treatment of chronic myeloid leukemia (CML), they generally fail to completely eradicate Bcr-Abl+ leukemia cells. To identify genes whose inhibition sensitizes Bcr-Abl+ leukemias to killing by Bcr-Abl inhibitors, we performed an RNAi-based synthetic lethal screen with imatinib in CML cells. This screen identified numerous components of a Wnt/Ca2+/NFAT signaling pathway. Antagonism of this pathway led to impaired NFAT activity, decreased cytokine production and enhanced sensitivity to Bcr-Abl inhibition. Furthermore, NFAT inhibition with cyclosporin A facilitated leukemia cell elimination by the Bcr-Abl inhibitor dasatinib and markedly improved survival in a mouse model of Bcr-Abl+ acute lymphoblastic leukemia (ALL). Targeting this pathway in combination with Bcr-Abl inhibition could improve treatment of Bcr-Abl+ leukemias. We utilized a genome-wide shRNA library in combination with microarray analysis to screen for gene targets in chronic myeloid leukemia cells that cooperate with imatinib.

2010-07-15 | E-GEOD-21499 | biostudies-arrayexpress

Identification of a novel lncRNA family that is required for efficient cellular transformation by Bcr-Abl oncogene

Project description:Aberrantly expressed long noncoding RNAs (lncRNAs) have been described in diverse human diseases and cancer development. Chronic myeloid leukemia (CML) is a hematological malignancy induced by Bcr-Abl hybrid gene. Owing to the development of tyrosine kinase inhibitors (TKIs), especially the first-generation Imatinib, over 90% of CML patients can be cured in recent years. Here we attempt to identify Imatinib-inducible lncRNAs associated with CML by analyzing lncRNA expression profiles in K562 cells after Imatinib or control treatment. LncRNA microarray analysis revealed that numerous lncRNAs were differentially expressed in K562 cells after Imatinib treatment. In this study, we focus on a conserved, Imatinib-inducible lncRNA (IIR) family, named lncRNA-IIRX. Upregulation of lncRNA-IIRX has been detected in both human and mouse Abl-transformed cell lines after Imatinib treatment. Interestingly, lncRNA-IIRX levels were significantly lower in leukemic cells derived from Bcr-Abl-positive ALL patients than those in normal control group. Furthermore, altering lncRNA-IIRX expression remarkably affected survival of Abl-transformed leukemic cells, and tumorigensis induced by these leukemic cells in xenograft mouse model. Knockdown of lncRNA-IIRX in transgenic mice significantly promoted Bcr-Abl-mediated primary bone marrow transformation, and leukemia development in leukemia mouse model. These results indicate that lncRNA-IIRX functions as a suppressor gene in Bcr-Abl-induced tumorigenesis, and may provide novel insights into complicated mechanisms underlying cellular transformation by Bcr-Abl oncogene. This microarray was performed to identify Imatinib-inducible lncRNAs associated with CML.

2019-04-17 | GSE119770 | GEO

Combination of multiomics approach and BCR-ABL based molecular testing: A better way to monitor treatment regimen and disease progression in Chronic Myeloid Leukemia [OncoScan]

Project description:We screened TKI-treated-CML-samples in different-phases based on < or >10% copies of BCR-ABL, undetected and control-samples for generating transcriptomics-profile. Transcriptionally, three clusters were identified which showed correlation with BCR-ABL transcript-levels i.e. <10% copies (I-cluster) , undetectable (II-cluster) and >10% copies (III-cluster).

2016-02-06 | GSE77571 | GEO

Combination of multiomics approach and BCR-ABL based molecular testing: A better way to monitor treatment regimen and disease progression in Chronic Myeloid Leukemia [HTA-2_0]

2016-01-26 | GSE77191 | GEO

Transcription profiling of four mouse cell lines with mutations in the oncogenic tyrosine kinase gene BCR-Abl

Project description:Gene expression profile variation between 4 BCR-Abl transduced cell lines: 1-Mouse DA1-3b cell line as reference, 2-DR1 imatinib resistant clone with E255K BCR-abl mutation 3-DRBMSR 2 dasatinib resistant clone with E255K and T315I BCR-Abl mutation. 4-DRBMSR 7 dasatinib resistant clone with E255K and T315I and V299L BCR-Abl mutation BCR-ABL is an oncogenic tyrosine kinase involved in the development of chronic myelogenous leukaemia (CML).

2007-08-01 | E-MEXP-772 | biostudies-arrayexpress

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