Abstract:
BACKGROUND:Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer and the leading cause of cancer-related mortality in children. T cell ALL (T-ALL) represents about 15% of pediatric ALL cases and is considered a high-risk disease. T-ALL is often associated with resistance to treatment, including steroids, which are currently the cornerstone for treating ALL; moreover, initial steroid response strongly predicts survival and cure. However, the cellular mechanisms underlying steroid resistance in T-ALL patients are poorly understood. In this study, we combined various genomic datasets in order to identify candidate genetic mechanisms underlying steroid resistance in children undergoing T-ALL treatment. METHODS AND FINDINGS:We performed whole genome sequencing on paired pre-treatment (diagnostic) and post-treatment (remission) samples from 13 patients, and targeted exome sequencing of pre-treatment samples from 69 additional T-ALL patients. We then integrated mutation data with copy number data for 151 mutated genes, and this integrated dataset was tested for associations of mutations with clinical outcomes and in vitro drug response. Our analysis revealed that mutations in JAK1 and KRAS, two genes encoding components of the interleukin 7 receptor (IL7R) signaling pathway, were associated with steroid resistance and poor outcome. We then sequenced JAK1, KRAS, and other genes in this pathway, including IL7R, JAK3, NF1, NRAS, and AKT, in these 69 T-ALL patients and a further 77 T-ALL patients. We identified mutations in 32% (47/146) of patients, the majority of whom had a specific T-ALL subtype (early thymic progenitor ALL or TLX). Based on the outcomes of these patients and their prednisolone responsiveness measured in vitro, we then confirmed that these mutations were associated with both steroid resistance and poor outcome. To explore how these mutations in IL7R signaling pathway genes cause steroid resistance and subsequent poor outcome, we expressed wild-type and mutant IL7R signaling molecules in two steroid-sensitive T-ALL cell lines (SUPT1 and P12 Ichikawa cells) using inducible lentiviral expression constructs. We found that expressing mutant IL7R, JAK1, or NRAS, or wild-type NRAS or AKT, specifically induced steroid resistance without affecting sensitivity to vincristine or L-asparaginase. In contrast, wild-type IL7R, JAK1, and JAK3, as well as mutant JAK3 and mutant AKT, had no effect. We then performed a functional study to examine the mechanisms underlying steroid resistance and found that, rather than changing the steroid receptor's ability to activate downstream targets, steroid resistance was associated with strong activation of MEK-ERK and AKT, downstream components of the IL7R signaling pathway, thereby inducing a robust antiapoptotic response by upregulating MCL1 and BCLXL expression. Both the MEK-ERK and AKT pathways also inactivate BIM, an essential molecule for steroid-induced cell death, and inhibit GSK3B, an important regulator of proapoptotic BIM. Importantly, treating our cell lines with IL7R signaling inhibitors restored steroid sensitivity. To address clinical relevance, we treated primary T-ALL cells obtained from 11 patients with steroids either alone or in combination with IL7R signaling inhibitors; we found that including a MEK, AKT, mTOR, or dual PI3K/mTOR inhibitor strongly increased steroid-induced cell death. Therefore, combining these inhibitors with steroid treatment may enhance steroid sensitivity in patients with ALL. The main limitation of our study was the modest cohort size, owing to the very low incidence of T-ALL. CONCLUSIONS:Using an unbiased sequencing approach, we found that specific mutations in IL7R signaling molecules underlie steroid resistance in T-ALL. Future prospective clinical studies should test the ability of inhibitors of MEK, AKT, mTOR, or PI3K/mTOR to restore or enhance steroid sensitivity and improve clinical outcome.
journal_name
PLoS Medjournal_title
PLoS medicineauthors
Li Y,Buijs-Gladdines JG,Canté-Barrett K,Stubbs AP,Vroegindeweij EM,Smits WK,van Marion R,Dinjens WN,Horstmann M,Kuiper RP,Buijsman RC,Zaman GJ,van der Spek PJ,Pieters R,Meijerink JPdoi
10.1371/journal.pmed.1002200subject
Has Abstractpub_date
2016-12-20 00:00:00pages
e1002200issue
12eissn
1549-1277issn
1549-1676pii
PMEDICINE-D-16-02492journal_volume
13pub_type
杂志文章相关文献
PLOS MEDICINE文献大全abstract:BACKGROUND:Research needs to be reported transparently so readers can critically assess the strengths and weaknesses of the design, conduct, and analysis of studies. Reporting guidelines have been developed to inform reporting for a variety of study designs. The objective of this study was to identify whether there is ...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1001069
更新日期:2010-08-01 00:00:00
abstract::In a Perspective, Lynn Morris and Nonhlanhla Mkhize discuss the prospects for broadly neutralizing antibodies to be used in preventing HIV infection. ...
journal_title:PLoS medicine
pub_type: 杂志文章,评审
doi:10.1371/journal.pmed.1002436
更新日期:2017-11-14 00:00:00
abstract:BACKGROUND:Drug manufacturers have developed "evergreening" strategies to compete with generic medication after patent termination. These include marketing of slightly modified follow-on drugs. We aimed to estimate the financial impact of these drugs on overall healthcare costs and also to examine the impact of listing...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1001460
更新日期:2013-01-01 00:00:00
abstract:BACKGROUND:The anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab improves outcomes in patients with node-positive HER2+ early breast cancer. Given trastuzumab's high cost, we aimed to estimate its cost-effectiveness by heterogeneity in age and estrogen receptor (ER) and progesterone r...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1002067
更新日期:2016-08-09 00:00:00
abstract:BACKGROUND:Standardised packaging (SP) of tobacco products is an innovative tobacco control measure opposed by transnational tobacco companies (TTCs) whose responses to the UK government's public consultation on SP argued that evidence was inadequate to support implementing the measure. The government's initial decisio...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1001629
更新日期:2014-03-25 00:00:00
abstract:BACKGROUND:Experimental studies have suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors provide cardiovascular protective effects. We performed a randomized study to evaluate the effects of sitagliptin added on to the conventional therapy compared with conventional therapy alone (diet, exercise, and/or drugs, exc...
journal_title:PLoS medicine
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1371/journal.pmed.1002051
更新日期:2016-06-28 00:00:00
abstract:BACKGROUND:In Botswana, an estimated 24% of adults ages 15-49 years are infected with HIV. While alcohol use is strongly associated with HIV infection in Africa, few population-based studies have characterized the association of alcohol use with specific high-risk sexual behaviors. METHODS AND FINDINGS:We conducted a ...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.0030392
更新日期:2006-10-01 00:00:00
abstract::Harald Schmidt and Anne Barnhill highlight the need to ensure equity in the proposed Sustainable Development Goals. ...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1001872
更新日期:2015-09-08 00:00:00
abstract:BACKGROUND:Preventive chemotherapy represents a powerful but short-term control strategy for soil-transmitted helminthiasis. Since humans are often re-infected rapidly, long-term solutions require improvements in water, sanitation, and hygiene (WASH). The purpose of this study was to quantitatively summarize the relati...
journal_title:PLoS medicine
pub_type: 杂志文章,meta分析,评审
doi:10.1371/journal.pmed.1001620
更新日期:2014-03-25 00:00:00
abstract::In a Policy Forum, Peter Hotez and colleagues discuss vaccination exemptions in US states and possible consequences for infectious disease outbreaks. ...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1002578
更新日期:2018-06-12 00:00:00
abstract:BACKGROUND:Through major efforts to reduce costs and expand access to antiretroviral therapy worldwide, widespread delivery of effective treatment to people living with HIV/AIDS is now conceivable even in severely resource-constrained settings. However, the potential epidemiologic impact of treatment in the context of ...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.0020016
更新日期:2005-01-01 00:00:00
abstract:BACKGROUND:Ovarian cancer kills approximately 15,000 women in the United States every year, and more than 140,000 women worldwide. Most deaths from ovarian cancer are caused by tumors of the serous histological type, which are rarely diagnosed before the cancer has spread. Rational design of a potentially life-saving e...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1000114
更新日期:2009-07-01 00:00:00
abstract:BACKGROUND:Evidence suggests that variations in fasting glucose and insulin amongst those without frank type 2 diabetes mellitus are important determinants of cardiovascular disease. However, the relative importance of variations in fasting insulin, glucose, and glycated haemoglobin as risk factors for cardiovascular d...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.0040263
更新日期:2007-08-01 00:00:00
abstract::This month in PLOS Medicine we launched a Special Issue on New Tools and Strategies for Tuberculosis Diagnosis, Care, and Elimination. In this issue's Editorial, the Guest Editors Claudia Denkinger, Richard Chaisson, and Mark Hatherill highlight some of the research that will publish and how these studies focusing on ...
journal_title:PLoS medicine
pub_type: 社论
doi:10.1371/journal.pmed.1002795
更新日期:2019-04-30 00:00:00
abstract:BACKGROUND:Introduction of pneumococcal conjugate vaccines (PCVs) of limited valency is justified in Africa by the high burden of pneumococcal disease. Long-term beneficial effects of PCVs may be countered by serotype replacement. We aimed to determine the impact of PCV-7 vaccination on pneumococcal carriage in rural G...
journal_title:PLoS medicine
pub_type: 杂志文章,随机对照试验
doi:10.1371/journal.pmed.1001107
更新日期:2011-10-01 00:00:00
abstract:BACKGROUND:Hepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection. METHODS AND FINDINGS:We measured T cell responsiveness...
journal_title:PLoS medicine
pub_type: 杂志文章,多中心研究
doi:10.1371/journal.pmed.0030492
更新日期:2006-12-01 00:00:00
abstract:BACKGROUND:Point-of-care CD4 tests at HIV diagnosis could improve linkage to care in resource-limited settings. Our objective is to evaluate the clinical and economic impact of point-of-care CD4 tests compared to laboratory-based tests in Mozambique. METHODS AND FINDINGS:We use a validated model of HIV testing, linkag...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1001725
更新日期:2014-09-16 00:00:00
abstract:BACKGROUND:The epidemiology of malaria makes surveillance-based methods of estimating its disease burden problematic. Cartographic approaches have provided alternative malaria burden estimates, but there remains widespread misunderstanding about their derivation and fidelity. The aims of this study are to present a new...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1000290
更新日期:2010-06-15 00:00:00
abstract::Kwonjune Seung and colleagues describe the Eugene Bell Foundation's experience of treating MDR-TB in North Korea. ...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1002062
更新日期:2016-08-02 00:00:00
abstract:BACKGROUND:Excessive pregnancy weight gain is associated with obesity in the offspring, but this relationship may be confounded by genetic and other shared influences. We aimed to examine the association of pregnancy weight gain with body mass index (BMI) in the offspring, using a within-family design to minimize confo...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1001521
更新日期:2013-10-01 00:00:00
abstract:BACKGROUND:Spurred by the creation of potential modified risk tobacco products, the US Food and Drug Administration (FDA) commissioned the Institute of Medicine (IOM) to assess the science base for tobacco "harm reduction," leading to the 2001 IOM report Clearing the Smoke. The objective of this study was to determine ...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1001450
更新日期:2013-01-01 00:00:00
abstract::Pharmacogenomics is one of the first clinical applications of the postgenomic era. It promises personalized medicine rather than the established "one size fits all" approach to drugs and dosages. The expected reduction in trial and error should ultimately lead to more efficient and safer drug therapy. In recent years,...
journal_title:PLoS medicine
pub_type: 杂志文章,评审
doi:10.1371/journal.pmed.0040209
更新日期:2007-08-01 00:00:00
abstract:BACKGROUND:The risk of perinatal death and severe neonatal morbidity increases gradually after 41 weeks of pregnancy. Several randomised controlled trials (RCTs) have assessed if induction of labour (IOL) in uncomplicated pregnancies at 41 weeks will improve perinatal outcomes. We performed an individual participant da...
journal_title:PLoS medicine
pub_type: 杂志文章,meta分析
doi:10.1371/journal.pmed.1003436
更新日期:2020-12-08 00:00:00
abstract:BACKGROUND:Tissue advanced glycation end product (AGE) accumulation has been proposed as a marker of cumulative metabolic stress that can be assessed noninvasively by measurement of skin autofluorescence (SAF). In persons on haemodialysis, SAF is an independent risk factor for cardiovascular events (CVEs) and all-cause...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1003163
更新日期:2020-07-13 00:00:00
abstract::[This corrects the article DOI: 10.1371/journal.pmed.1002781.]. ...
journal_title:PLoS medicine
pub_type: 已发布勘误
doi:10.1371/journal.pmed.1002880
更新日期:2019-07-18 00:00:00
abstract:BACKGROUND:Published research on prescribed opioid analgesic (POA) use during pregnancy and birth outcomes is limited in scope and has not adequately adjusted for potential confounding factors. To help address these gaps, we estimated associations between maternal POAs during pregnancy and two adverse birth outcomes us...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1002980
更新日期:2019-12-02 00:00:00
abstract:BACKGROUND:Epidemiological studies have provided compelling evidence of associations between ambient temperature and cardiovascular disease. However, evidence of effects of daily temperature variability on cardiovascular disease is scarce and mixed. We aimed to examine short-term associations between temperature variab...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1002738
更新日期:2019-01-28 00:00:00
abstract:BACKGROUND:Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associ...
journal_title:PLoS medicine
pub_type: 杂志文章,meta分析,评审
doi:10.1371/journal.pmed.1001680
更新日期:2014-07-22 00:00:00
abstract:BACKGROUND:Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would b...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1001628
更新日期:2014-04-15 00:00:00
abstract:BACKGROUND:There is an urgent need to identify tools able to provide reliable information on the cause of death in low-income regions, since current methods (verbal autopsy, clinical records, and complete autopsies) are either inaccurate, not feasible, or poorly accepted. We aimed to compare the performance of a standa...
journal_title:PLoS medicine
pub_type: 杂志文章
doi:10.1371/journal.pmed.1002171
更新日期:2016-11-22 00:00:00