Abstract:
:Overcoming drug resistance and targeting leukemic stem cells (LSCs) remain major challenges in curing BCR-ABL+ human leukemia. Using an advanced drug/proliferation screen, we have uncovered a prosurvival role for protein phosphatase 2A (PP2A) in tyrosine kinase inhibitor (TKI)-insensitive leukemic cells, regulated by an Abelson helper integration site-1-mediated PP2A-β-catenin-BCR-ABL-JAK2 protein complex. Genetic and pharmacological inhibition of PP2A impairs survival of TKI nonresponder cells and sensitizes them to TKIs in vitro, inducing a dramatic loss of several key proteins, including β-catenin. We also demonstrate that the clinically validated PP2A inhibitors LB100 and LB102, in combination with TKIs, selectively eliminate treatment-naïve TKI-insensitive stem and progenitor cells, while sparing healthy counterparts. In addition, PP2A inhibitors and TKIs act synergistically to inhibit the growth of TKI-insensitive cells, as assessed by combination index analysis. The combination eliminates infiltrated BCR-ABL+ blast cells and drug-insensitive LSCs and confers a survival advantage in preclinical xenotransplant models. Thus, dual PP2A and BCR-ABL inhibition may be a valuable therapeutic strategy to synergistically target drug-insensitive LSCs that maintain minimal residual disease in patients.
journal_name
Sci Transl Medjournal_title
Science translational medicineauthors
Lai D,Chen M,Su J,Liu X,Rothe K,Hu K,Forrest DL,Eaves CJ,Morin GB,Jiang Xdoi
10.1126/scitranslmed.aan8735subject
Has Abstractpub_date
2018-02-07 00:00:00issue
427eissn
1946-6234issn
1946-6242pii
10/427/eaan8735journal_volume
10pub_type
杂志文章abstract::Depending on age of acquisition, hepatitis B virus (HBV) can induce a cell-mediated immune response that results in either cure or progressive liver injury. In adult-acquired infection, HBV antigens are usually cleared, whereas in infancy-acquired infection, they persist. Individuals infected during infancy therefore ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aah5766
更新日期:2018-03-21 00:00:00
abstract::Recent studies have established the involvement of the fat mass and obesity-associated gene (FTO) in metabolic disorders such as obesity and diabetes. However, the precise molecular mechanism by which FTO regulates metabolism remains unknown. Here, we used a structure-based virtual screening of U.S. Food and Drug Admi...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aau7116
更新日期:2019-04-17 00:00:00
abstract::Troublesome involuntary movements in the absence of dopaminergic medication, so-called off-medication dyskinesias, are a serious adverse effect of fetal neural grafts that hinders the development of cell-based therapies for Parkinson's disease. The mechanisms underlying these dyskinesias are not well understood, and i...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3000976
更新日期:2010-06-30 00:00:00
abstract::Graft-versus-host disease (GVHD) is the most common complication of hematopoietic stem cell transplant (HCT). However, our understanding of the molecular pathways that cause this disease remains incomplete, leading to inadequate treatment strategies. To address this, we measured the gene expression profile of nonhuman...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aad3231
更新日期:2015-11-25 00:00:00
abstract::Late infantile Batten disease (CLN2 disease) is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations in the CLN2 gene encoding tripeptidyl peptidase 1 (TPP1). We tested intraparenchymal delivery of AAVrh.10hCLN2, a nonhuman serotype rh.10 adeno-associated virus vector encoding human ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.abb5413
更新日期:2020-12-02 00:00:00
abstract::The aim of treatment in congenital adrenal hyperplasia is to suppress excess adrenal androgens while achieving physiological glucocorticoid replacement. However, current glucocorticoid replacement regimes are inadequate because doses sufficient to suppress excess androgens almost invariably induce adverse metabolic ef...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaf9074
更新日期:2016-08-17 00:00:00
abstract::Osteoclasts actively remodel both the mineral and proteinaceous components of bone during normal growth and development as well as pathologic states ranging from osteoporosis to bone metastasis. The cysteine proteinase cathepsin K confers osteoclasts with potent type I collagenolytic activity; however, cathepsin K-nul...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaw6143
更新日期:2020-02-05 00:00:00
abstract::Axonal dystrophy, indicative of perturbed axonal transport, occurs early during Alzheimer's disease (AD) pathogenesis. Little is known about the mechanisms underlying this initial sign of the pathology. This study proves that Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) loss of function, due to Gga3 g...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aba1871
更新日期:2020-11-18 00:00:00
abstract::The development of new approaches to cholera control relies on an accurate understanding of cholera epidemiology. However, most information on cholera incidence lacks laboratory confirmation and instead relies on surveillance systems reporting medically attended acute watery diarrhea. If recent infections could be ide...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aau6242
更新日期:2019-02-20 00:00:00
abstract::Motor neuron-specific microRNA-218 (miR-218) has recently received attention because of its roles in mouse development. However, miR-218 relevance to human motor neuron disease was not yet explored. Here, we demonstrate by neuropathology that miR-218 is abundant in healthy human motor neurons. However, in amyotrophic ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aav5264
更新日期:2019-12-18 00:00:00
abstract::Current HIV vaccines are only partially efficacious, presenting an opportunity to identify correlates of protection and, thereby, potential insight into mechanisms that prevent HIV acquisition. Two independent preclinical challenge studies in nonhuman primates (NHPs) previously showed partial efficacy of a mosaic aden...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaw4236
更新日期:2019-08-28 00:00:00
abstract::Antiretroviral therapy has improved the quality and length of life of millions of individuals affected by human immunodeficiency virus type 1 (HIV-1). The capacity of these drugs to indefinitely suppress HIV-which has a well-known capacity for escaping antiviral pressures-is surprising. In this issue of Science Transl...
journal_title:Science translational medicine
pub_type: 评论,杂志文章
doi:10.1126/scitranslmed.3002656
更新日期:2011-07-13 00:00:00
abstract::A clinical trial evaluating HIV vaccine therapy teaches us much about optimal design (Sneller et al, this issue). ...
journal_title:Science translational medicine
pub_type: 杂志文章,评审
doi:10.1126/scitranslmed.aaq0810
更新日期:2017-12-06 00:00:00
abstract::Alzheimer's disease (AD) is hypothesized to be caused by an overproduction or reduced clearance of amyloid-β (Aβ) peptide. Autosomal dominant AD (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of Aβ42 compared to Aβ40 in the central nervous system (CNS)...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3005615
更新日期:2013-06-12 00:00:00
abstract::Physiological data are routinely recorded in intensive care, but their use for rapid assessment of illness severity or long-term morbidity prediction has been limited. We developed a physiological assessment score for preterm newborns, akin to an electronic Apgar score, based on standard signals recorded noninvasively...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3001304
更新日期:2010-09-08 00:00:00
abstract::Restoring reverse cholesterol transport ameliorates the B cell hyperexpansion and autoimmune disease found to be associated with accumulation of cholesterol in CD11c+ antigen-presenting cells. ...
journal_title:Science translational medicine
pub_type: 评论,杂志文章
doi:10.1126/scitranslmed.aal4997
更新日期:2017-01-25 00:00:00
abstract::Increased DNA breaks in aging skeletal muscle activate the DNA-PK pathway, whereas blocking this pathway improves mitochondrial density, physical fitness, body weight, and insulin resistance in mice. ...
journal_title:Science translational medicine
pub_type: 评论,杂志文章
doi:10.1126/scitranslmed.aan4290
更新日期:2017-05-17 00:00:00
abstract::Whole-genome sequencing of patient DNA can facilitate diagnosis of a disease, but its potential for guiding treatment has been under-realized. We interrogated the complete genome sequences of a 14-year-old fraternal twin pair diagnosed with dopa (3,4-dihydroxyphenylalanine)-responsive dystonia (DRD; Mendelian Inherita...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3002243
更新日期:2011-06-15 00:00:00
abstract::Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T cell activation. Although evidence for an active immune response, including infiltration with CD8(+) T cells, can be found in a subset of patients, those tumors are nonetheless not immunologically rejecte...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3006504
更新日期:2013-08-28 00:00:00
abstract::Misuse of prescription opioids, opioid addiction, and overdose underscore the urgent need for developing addiction-free effective medications for treating severe pain. Mu opioid peptide (MOP) receptor agonists provide very effective pain relief. However, severe side effects limit their use in the clinical setting. Ago...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aar3483
更新日期:2018-08-29 00:00:00
abstract::Disease-free infection in HIV-infected adults is associated with human leukocyte antigen-mediated suppression of viremia, whereas in the sooty mangabey and other healthy natural hosts of simian immunodeficiency virus (SIV), viral replication continues unabated. To better understand factors preventing HIV disease, we i...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aag1048
更新日期:2016-09-28 00:00:00
abstract::Amine-containing polymers immobilized on mesh and placed at trauma sites scavenge biomolecules that initiate a damaging immune response. ...
journal_title:Science translational medicine
pub_type: 评论,杂志文章
doi:10.1126/scitranslmed.aam6068
更新日期:2017-02-22 00:00:00
abstract::Promising therapies for cartilage repair are translated through large animal models toward human application. To guide this work, regulatory agencies publish recommendations ("guidance documents") to direct pivotal large animal studies. These are meant to aid in study design, outline metrics for judging efficacy, and ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aac7019
更新日期:2015-10-21 00:00:00
abstract::Epidermal growth factor receptor (EGFR) gene mutations (G719X, exon 19 deletions/insertions, L858R, and L861Q) predict favorable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). However, EGFR exon 20 insertion mutations (~10% of all EGFR mutations) are generally assoc...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3007205
更新日期:2013-12-18 00:00:00
abstract::Variants in the leucine-rich repeat kinase-2 (LRRK2) gene are associated with Parkinson's disease, leprosy, and Crohn's disease, three disorders with inflammation as an important component. Because of its high expression in granulocytes and CD68-positive cells, LRRK2 may have a function in innate immunity. We tested t...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aas9292
更新日期:2019-09-25 00:00:00
abstract::Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetyl-aspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of p...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3003454
更新日期:2012-12-19 00:00:00
abstract::Recent studies highlighted long noncoding RNAs (lncRNAs) to play an important role in cardiac development. However, understanding of lncRNAs in cardiac diseases is still limited. Global lncRNA expression profiling indicated that several lncRNA transcripts are deregulated during pressure overload-induced cardiac hypert...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaf1475
更新日期:2016-02-17 00:00:00
abstract::Understanding the biological properties of plasma cell-free DNA may expand its applications in oncology (Mouliere et al, this issue). ...
journal_title:Science translational medicine
pub_type: 评论,杂志文章,评审
doi:10.1126/scitranslmed.aav3873
更新日期:2018-11-07 00:00:00
abstract::Research standards deviate in genetic versus nongenetic epidemiology. Besides some immutable differences, such as the correlation pattern between variables, these divergent research standards can converge considerably. Current research designs that dissociate genetic and nongenetic measurements are reaching their limi...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3000247
更新日期:2009-11-18 00:00:00
abstract::The inability to produce perfusable microvasculature networks capable of supporting tissue survival and of withstanding physiological pressures without leakage is a fundamental problem facing the field of tissue engineering. Microvasculature is critically important for production of bioengineered lung (BEL), which req...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aao3926
更新日期:2018-08-01 00:00:00