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Transcription profiling of human bone marrow from primary multiple myeloma patients

ABSTRACT: Drug resistance is a major obstacle in cancer therapy. The molecular mechanisms of drug resistance still remain largely elusive. Microarray analyses on paired primary myeloma samples at baseline and after therapy or at relapse showed that NEK2 was one of the most up-regulated genes in myeloma cells after high-dose chemotherapy or at relapse. By analyzing the published (> 2,500) microarrays and clinical datasets, we found that NEK2 expression is increased in many malignancies, and that high expression of NEK2 was associated with a shorter event-free and overall survival. Moreover, NEK2 expression was typically increased in tumors with aggressive subtype and advanced TNM stage. Our studies indicate that over-expressing NEK2 in cancer cells resulted in enhanced cell proliferation and drug resistance, whereas knockdown of NEK2 induced significant cancer cell death and growth inhibition. We found that NEK2 over-expression activates cell cycle progression and cell division through the stimulation of cell cycling genes CDC2/CCNB1 and PBK. Interestingly, NEK2-overexpression also activated the Wnt/Î²-catenin signaling pathway. We conclude that NEK2 represents a predictor for drug resistance and poor prognosis in cancers and could be a potential target for cancer therapy. Experiment Overall Design: Myeloma tumor cells from bone marrow aspirates were collected at baseline and after chemotherapy (pre-1st and pre-2nd bone marrow transplant, and pre-consolidation) for RNA extraction and hybridization on Affymetrix microarrays. We sought to define genes related to chemotheraputic resistance.

ORGANISM(S): Homo sapiens

SUBMITTER: fenghuang zhan

PROVIDER: E-GEOD-19554 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression data from bone marrow of primary multiple myeloma patients

Project description:Drug resistance is a major obstacle in cancer therapy. The molecular mechanisms of drug resistance still remain largely elusive. Microarray analyses on paired primary myeloma samples at baseline and after therapy or at relapse showed that NEK2 was one of the most up-regulated genes in myeloma cells after high-dose chemotherapy or at relapse. By analyzing the published (> 2,500) microarrays and clinical datasets, we found that NEK2 expression is increased in many malignancies, and that high expression of NEK2 was associated with a shorter event-free and overall survival. Moreover, NEK2 expression was typically increased in tumors with aggressive subtype and advanced TNM stage. Our studies indicate that over-expressing NEK2 in cancer cells resulted in enhanced cell proliferation and drug resistance, whereas knockdown of NEK2 induced significant cancer cell death and growth inhibition. We found that NEK2 over-expression activates cell cycle progression and cell division through the stimulation of cell cycling genes CDC2/CCNB1 and PBK. Interestingly, NEK2-overexpression also activated the Wnt/β-catenin signaling pathway. We conclude that NEK2 represents a predictor for drug resistance and poor prognosis in cancers and could be a potential target for cancer therapy.

2013-01-22 | GSE19554 | GEO

Osteoclasts Control Re-activation of Dormant Myeloma Cells by Remodeling the Endosteal Niche

Project description:Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specialized niches, which resist therapy and re-populate the tumor. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and re-activation. In this study we track individual myeloma cells by intravital imaging as they colonize the endosteal niche, enter a dormant state and subsequently become activated to form colonies. We demonstrate that dormancy is a reversible state which is switched ‘on’ by engagement with bone lining cells or osteoblasts, and switched ‘off’ by osteoclasts remodeling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy targeting dividing cells. The demonstration that the endosteal niche is pivotal in controlling myeloma cell dormancy highlights the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistance and prevent disease relapse.

2015-11-30 | GSE57695 | GEO

Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma

Project description:The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are highly effective treatments for multiple myeloma. However, virtually all patients eventually relapse due to acquired drug resistance with resistance-causing genetic alterations being found only in a small subset of cases. Here, we performed integrated global quantitative tandem mass tag (TMT)-based proteomic and phosphoproteomic analyses and RNA sequencing in five paired pre-treatment and relapse samples from multiple myeloma patients to investigate non-genetic resistance mechanisms. These analyses revealed a CDK6-governed protein resistance signature that includes myeloma high-risk factors such as TRIP13 and RRM1. Overexpression of CDK6 in multiple myeloma cell lines reduced sensitivity to IMiDs while CDK6 inhibition by palbociclib or CDK6 degradation by proteolysis targeting chimeras (PROTACs) is highly synergistic with IMiDs in vitro and in vivo. In conclusion, we found upregulation of CDK6 to cause lenalidomide resistance in multiple myeloma that can be overcome by pharmacological intervention.

2021-12-17 | PXD021265 | Pride

Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma

Project description:Multiple myeloma is a genetically heterogeneous disease of plasma cells. The thalidomide analog lenalidomide is a mainstay in the treatment of multiple myeloma and is used in combination with other drugs such as corticosteroids, chemotherapy and proteasome inhibitors, achieving high remission rates. However, most patients relapse due to acquired resistance of the malignant cells. Genetic analyses have revealed mutations in CRBN, the target of all IMiDs, as a resistance mechanism in 10% of patients, while for the majority of cases, the mechanism of resistance is unknown. Here, we performed integrated global quantitative tandem mass tag (TMT)-based proteomic and phosphoproteomic analyses and RNA sequencing in five paired pre-treatment and relapse samples from multiple myeloma patients. These analyses revealed proteins highly upregulated at relapse, including TRIP13, RRM1 and CDK6, which was not reflected on the RNA expression level. Overexpression of CDK6 in multiple myeloma cell lines reduced sensitivity to lenalidomide and pomalidomide in a kinase-dependent fashion. CDK6 inactivation by palbociclib or a CDK6-specific proteolysis targeting chimera (PROTAC) plus lenalidomide or pomalidomide was highly synergistic. Proteomic analyses in cell lines revealed that CDK6 inhibition reverses a complex protein resistance signature including RRM1 and TRIP13 and in combination with IMiDs promotes metabolic remodeling and c-MYC downregulation . In conclusion, our global proteomic analyses identified CDK6 upregulation as a drug target to overcome lenalidomide resistance in multiple myeloma.

2021-12-14 | GSE162403 | GEO

Validation cohort for genomic predictor of response and survival following neoadjuvant taxane-anthracycline chemotherapy in breast cancer

Project description:PURPOSE: To develop a predictive test for response and survival following neoadjuvant taxane-anthracycline chemotherapy for HER2-negative invasive breast cancer. METHODS: We developed a microarray-based gene expression test from pre-treatment tumor biopsies (310 patients) to predict favorable outcome based on estrogen receptor (ER) status,pathologic response to chemotherapy, 3-year disease outcomes, and sensitivity to endocrine therapy. Tumors were classified as treatment-sensitive if predicted to have pathologic response (and not resistance) to chemotherapy, or sensitive to endocrine therapy. We tested predictive accuracy, with 95% confidence interval (CI), for pathologic response (PPV, positive predictive value), distant relapse-free survival (DRFS), and absolute risk reduction at median follow-up in 198 other patients. Independence from clinical-pathologic factors was assessed in a multivariate Cox regression analysis based on the likelihood ratio test. Other evaluable, published response predictors (genomic grade index (GGI), intrinsic subtype (PAM50), pCR predictor (DLDA30)) were compared. Neoadjuvant validation cohort of 198 HER2-negative breast cancer cases treated with taxane-anthracycline chemotherapy pre-operatively and endocrine therapy if ER-positive. Response was assessed at the end of neoadjuvant treatment and distant-relapse-free survival was followed for at least 3 years post-surgery.

2011-05-11 | E-GEOD-25065 | biostudies-arrayexpress

Discovery cohort for genomic predictor of response and survival following neoadjuvant taxane-anthracycline chemotherapy in breast cancer

Project description:PURPOSE: To develop a predictive test for response and survival following neoadjuvant taxane-anthracycline chemotherapy for HER2-negative invasive breast cancer. METHODS: We developed a microarray-based gene expression test from pre-treatment tumor biopsies (310 patients) to predict favorable outcome based on estrogen receptor (ER) status,pathologic response to chemotherapy, 3-year disease outcomes, and sensitivity to endocrine therapy. Tumors were classified as treatment-sensitive if predicted to have pathologic response (and not resistance) to chemotherapy, or sensitive to endocrine therapy. We tested predictive accuracy, with 95% confidence interval (CI), for pathologic response (PPV, positive predictive value), distant relapse-free survival (DRFS), and absolute risk reduction at median follow-up in 198 other patients. Independence from clinical-pathologic factors was assessed in a multivariate Cox regression analysis based on the likelihood ratio test. Other evaluable, published response predictors (genomic grade index (GGI), intrinsic subtype (PAM50), pCR predictor (DLDA30)) were compared. Neoadjuvant study of 310 HER2-negative breast cancer cases treated with taxane-anthracycline chemotherapy pre-operatively and endocrine therapy if ER-positive. Response was assessed at the end of neoadjuvant treatment and distant-relapse-free survival was followed for at least 3 years post-surgery.

2011-05-11 | E-GEOD-25055 | biostudies-arrayexpress

Expression data from primary multiple myeloma plasma cells from patients treated by Total Therapy 2, 3 and Other protocols at baseline and relapse.

Project description:Global gene expression profile of primary multiple myeloma plasma cells from patients treated in Myeloma Institute for Research and Therapy was done using Affymetrix microarrays. MMPC were isolated from patients following Total Therapy 2, 3 and Other treatments at baseline and/or after relapse and GEP was done.

2015-08-13 | E-GEOD-31161 | biostudies-arrayexpress

Thalidomide in Total Therapy 2 Overcomes Inferior Prognosis of Myeloma with Low Expression of the Glucocorticoid Receptor Gene NR3C1

Project description:Purpose: Because dexamethasone remains a key component of myeloma therapy, we wished to examine the correlation of baseline and relapse expression levels of the glucocorticoid receptor gene NR3C1 with other clinical features. Experimental Design: We investigated the clinical impact of gene expression profiling (GEP)–derived expression levels of NR3C1 in 351 patients with GEP data available at baseline and in 130 with data available at relapse, among 668 subjects accrued to Total Therapy 2 (TT2). The effect of the expression of NR3C1 at baseline (previously published under GSE2685) and at relapse was analyzed in the context of treatment (thalidomide vs. no thalidomide) and other clinical parameters.

2012-11-05 | E-GEOD-38627 | biostudies-arrayexpress

Targeting Taxane-Platin Resistant Lung Cancers with JumonjiC Lysine Demethylase Inhibitors

Project description:While taxane-platin standard chemotherapy provides benefit in advanced and localized non-small cell lung cancer (NSCLC), the majority of patients relapse with drug resistant tumors. Mechanisms underlying NSCLC resistance to this standard doublet chemotherapy are still not fully understood, and treatment options for chemoresistant lung tumors are limited. The goals of this work were to establish new preclinical NSCLC models of resistance to taxane-platin doublet chemotherapy, identify mechanisms of resistance, and develop new rational pharmacologic approaches to target drug resistant NSCLCs.

2016-12-31 | GSE77209 | GEO

Clonal selection and double hit events involving tumor suppressor genes underlie relapse from chemotherapy: myeloma as a model

Project description:To elucidate the mechanisms underlying relapse from chemotherapy in multiple myeloma we performed a longitudinal study of 33 patients entered into Total Therapy protocols investigating them using gene expression profiling, high resolution copy number arrays and whole exome sequencing. The study illustrates the mechanistic importance of acquired mutations in known myeloma driver genes and the critical nature of bi-allelic inactivation events affecting tumor suppressor genes, especially TP53. The end result being resistance to apoptosis and increased proliferation rates, which drive relapse by Darwinian type clonal evolution. The number of copy number aberration changes and bi-allelic inactivation of tumor suppressor genes was increased in GEP70 high risk, consistent with genomic instability being a key feature of high risk. In conclusion, the study highlights the impact of acquired genetic events, which enhance the evolutionary fitness level of myeloma propagating cells to survive multi-agent chemotherapy and to result in relapse.

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