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Gene expression signature that predicts early molecular response failure in chronic phase CML patients on frontline imatinib

ABSTRACT: Gene expression signature that predicts early molecular response failure in chronic phase CML patients on frontline imatinib

PROVIDER: PRJNA540069 | ENA |

REPOSITORIES: ENA

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Gene expression signature that predicts early molecular response failure in chronic phase CML patients on frontline imatinib

Project description:In chronic phase chronic myeloid leukemia (CP-CML) patients treated with frontline imatinib, failure to achieve early molecular response (EMR failure: BCR-ABL1 >10% (IS) at 3 months) is predictive of inferior outcomes. Identifying patients at high-risk of EMR failure at diagnosis provides an opportunity to intensify frontline therapy and potentially avoid EMR failure. We studied blood samples from 96 CP-CML patients at diagnosis and identified 365 genes that were aberrantly expressed in 13 patients who subsequently failed to achieve EMR, with a gene signature significantly enriched for stem cell phenotype (e.g. Myc, b-catenin, Hoxa9/Meis1), cell cycle, and reduced immune response pathways. We selected a 17-gene panel to predict EMR failure and validated this signature on an independent patient cohort. Patients classified as high-risk with our gene expression signature (HR-GES) exhibited significantly higher rates of EMR failure compared to low-risk (LR-GES) patients (78% vs 5%; p<0.0001) with an overall accuracy of 93%. Furthermore, HR-GES patients who received frontline nilotinib had a relatively low rate of EMR failure (10%). However HR-GES patients still had inferior deep molecular response achievement rate by 24 months compared to LR-GES patients. This novel multi-gene signature may be useful for selecting patients at high risk of EMR failure on standard therapy, who may benefit from trials of more potent kinase inhibitors or other experimental approaches.

2019-05-29 | GSE130404 | GEO

EXPRESSION SIGNATURE TO PREDICT MAJOR CYTOGENETIC RESPONSE IN CHRONIC PHASE CML PATIENTS TREATED WITH IMATINIB

Project description:Newly diagnosed chronic phase chronic myeloid leukemia (CML) patients with a major cytogenetic response (MCyR) after 12 months of imatinib therapy have an excellent long-term outcome, while patients without MCyR have a high progression risk. Since patients with primary cytogenetic resistance may benefit from more intensive therapy up-front, we sought to identify biomarkers to predict MCyR. Keywords: Two group comparison to identify trasncriptomic signature that predicts response to therapy

2010-01-01 | GSE14671 | GEO

Transcription profiling of human chromic myeloid leukemia (CML) patients treated second-line with imatinib after failure of an interferon-alpha based therapy to identify genes with predictive value for primary cytogenetic outcome to imatinib

Project description:Identification of genes in CML patients with predictive value for their primary cytogenetic outcome to imatinib. All samples analyzed were taken just before the start of imatinib treatment. Leukemic patients were treated second-line with imatinib after failure of an interferon-alpha based therapy (first-line regimen).

2006-05-31 | E-MEXP-433 | biostudies-arrayexpress

Gene expression-based imatinib response prediction in chronic phase CML

Project description:Tyrosine kinase inhibitor (TKI) treatment of chronic myeloid leukemia (CML) is guided by the pre-defined European Leukemia Net (ELN) or other response criteria. This allows patient stratification only during but not prior to treatment initiation. Gene expression profiling (GEP)-based response prediction might become a valuable tool for patient stratification in CML, but so far published data for response prediction are conflicting. We generated an imatinib response predicting gene signature by GEP from peripheral blood samples of pre-treated CML patients in late chronic phase.

2021-12-31 | GSE44589 | GEO

miRNAs expression profiling in circulating lymphocytes of CML patients after imatinib discontinuation

Project description:Some chronic myeloid leukemia (CML) patients with complete molecular response (CMR) are considered able to sustain the CMR after imatinib discontinuation (STOP-IM). Mahon et al. reported that among patients with a CMR lasting at least 2 consecutive years, the CMR was sustained in 41% after imatinib discontinuation. To more appropriately identify patients who can safely discontinue imatinib, we assessed the miRNA profiles of CML patients. We compared CML patients who sustained CMR for more than 6 months after discontinuation of imatinib (STOP-IM group) with those who were receiving imatinib with CMR (currently called as UMD: undetermined minimal disease), and with healthy volunteers (controls).

2014-05-15 | GSE47652 | GEO

Gene expression analysis of chronic myeloid leukemic stem cells and progenitor cells from untreated and imatinib-treated CML-like mice

Project description:To understand gene expression signatures of CML stem cells underlying imatinib-resistance, we compared transcriptomes of CML stem and progenitor cells from vehicle and imatinib-treated CML mice, respectively.

2021-05-23 | GSE175323 | GEO

Expression profiling in extracellular miRNAs (plasma miRNAs) of CML patients after imatinib discontinuation (STOP-IM)

Project description:An approximately 40% of chronic myeloid leukemia (CML) patients who discontinued imatinib (IM) therapy maintained undetectable minimal residual disease (UMRD) for more than one year (STOP-IM). We set out to examine plasma miRNAs expression in CML patients who could discontinue IM, to seek the possible distinguishable biomarker in STOP-IM CML patients. We compared CML patients who sustained UMRD for more than one year after discontinuation of imatinib (STOP-IM group) with healthy volunteers (controls).

2016-03-31 | GSE75391 | GEO

Expression profiling in extracellular miRNAs (exosomal miRNAs) of CML patients after imatinib discontinuation (STOP-IM)

Project description:An approximately 40% of chronic myeloid leukemia (CML) patients who discontinued imatinib (IM) therapy maintained undetectable minimal residual disease (UMRD) for more than one year (STOP-IM). We therefore set out to examine exosomal miRNAs expression in CML patients who could discontinue IM, to seek the possible distinguishable biomarker in STOP-IM CML patients. We compared CML patients who sustained UMRD for more than one year after discontinuation of imatinib (STOP-IM group) with healthy volunteers (controls).

2016-03-31 | GSE75389 | GEO

Gene expression of CML CD34+ cells during Imatinib therapy

Project description:Imatinib has become the current standard therapy for patients with chronic myelogenous leukaemia (CML). For a better understanding of the Imatinib-related molecular effects in vivo, we assessed gene expression profiles of Philadelphia Chromosome positive (Ph+) CD34+ cells from peripheral blood of 6 patients with de novo CML in chronic phase. After 7 days of treatment with Imatinib the Ph+ CD34+ cells were reassessed to look for changes in the transcriptome. The expression level of 303 genes was significantly different comparing the transcriptome of the Ph+ CD34+ cells before and after 7 days of Imatinib therapy (183 down-regulated, 120 up-regulated, lower bound ≥1.2-fold). For a substantial number of genes governing cell cycle and DNA replication, the level of expression significantly decreased (CDC2, RRM2, PCNA, MCM4). On the other hand, therapy with Imatinib was associated with an increase of genes related to adhesive interactions, such as L-selectin or CD44. A group of 8 genes with differential expression levels were confirmed using a gene specific quantitative real-time PCR. Thus, during the first week of treatment, Imatinib is preferentially counteracting the bcr-abl induced effects related to a disturbed cell cycle and defective adhesion of leukemic Ph+ CD34+ cells.

2008-07-30 | GSE12211 | GEO

Transcription profiling of human CML CD34+ cells during Imatinib therapy

Project description:Imatinib has become the current standard therapy for patients with chronic myelogenous leukaemia (CML). For a better understanding of the Imatinib-related molecular effects in vivo, we assessed gene expression profiles of Philadelphia Chromosome positive (Ph+) CD34+ cells from peripheral blood of 6 patients with de novo CML in chronic phase. After 7 days of treatment with Imatinib the Ph+ CD34+ cells were reassessed to look for changes in the transcriptome. The expression level of 303 genes was significantly different comparing the transcriptome of the Ph+ CD34+ cells before and after 7 days of Imatinib therapy (183 down-regulated, 120 up-regulated, lower bound â¥1.2-fold). For a substantial number of genes governing cell cycle and DNA replication, the level of expression significantly decreased (CDC2, RRM2, PCNA, MCM4). On the other hand, therapy with Imatinib was associated with an increase of genes related to adhesive interactions, such as L-selectin or CD44. A group of 8 genes with differential expression levels were confirmed using a gene specific quantitative real-time PCR. Thus, during the first week of treatment, Imatinib is preferentially counteracting the bcr-abl induced effects related to a disturbed cell cycle and defective adhesion of leukemic Ph+ CD34+ cells. Experiment Overall Design: In total 6 patients with new diagnosis CML (Chronic Myelogenous Leukemia) in chronic phase are inculded in the study. The gene expression profiles of the CD34+ hematopoietic stem and progenitor cells from the patients before first treatment with Glivec (Imatinib) are compared to the gene expression profiles of the CD34+ hematopoietic stem and progenitor cells of the same patients after 7 days of treatment with 400 mg Glivec / day.

2008-10-21 | E-GEOD-12211 | biostudies-arrayexpress

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