Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL.

Abstract:

:Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Among chemotherapeutics, thiopurines are key drugs in ALL combination therapy. Using whole-exome sequencing, we identified relapse-specific mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes a rate-limiting purine biosynthesis enzyme, in 24/358 (6.7%) relapsed childhood B cell ALL (B-ALL) cases. All individuals who harbored PRPS1 mutations relapsed early during treatment, and mutated ALL clones expanded exponentially before clinical relapse. Our functional analyses of PRPS1 mutants uncovered a new chemotherapy-resistance mechanism involving reduced feedback inhibition of de novo purine biosynthesis and competitive inhibition of thiopurine activation. Notably, the de novo purine synthesis inhibitor lometrexol effectively abrogated PRPS1 mutant-driven drug resistance. These results highlight the importance of constitutive activation of the de novo purine synthesis pathway in thiopurine resistance, and they offer therapeutic strategies for the treatment of relapsed and thiopurine-resistant ALL.

journal_name

Nat Med

journal_title

Nature medicine

authors

Li B,Li H,Bai Y,Kirschner-Schwabe R,Yang JJ,Chen Y,Lu G,Tzoneva G,Ma X,Wu T,Li W,Lu H,Ding L,Liang H,Huang X,Yang M,Jin L,Kang H,Chen S,Du A,Shen S,Ding J,Chen H,Chen J,von Stackelberg A,Gu L,Zhang J,

doi

10.1038/nm.3840

subject

Has Abstract

pub_date

2015-06-01 00:00:00

pages

563-71

issue

6

eissn

1078-8956

issn

1546-170X

pii

nm.3840

journal_volume

21

pub_type

杂志文章
  • Automated subcellular localization and quantification of protein expression in tissue microarrays.

    abstract::The recent development of tissue microarrays-composed of hundreds of tissue sections from different tumors arrayed on a single glass slide-facilitates rapid evaluation of large-scale outcome studies. Realization of this potential depends on the ability to rapidly and precisely quantify the protein expression within ea...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm791

    authors: Camp RL,Chung GG,Rimm DL

    更新日期:2002-11-01 00:00:00

  • A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors.

    abstract::Single-cell genomics is essential to chart tumor ecosystems. Although single-cell RNA-Seq (scRNA-Seq) profiles RNA from cells dissociated from fresh tumors, single-nucleus RNA-Seq (snRNA-Seq) is needed to profile frozen or hard-to-dissociate tumors. Each requires customization to different tissue and tumor types, posi...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/s41591-020-0844-1

    authors: Slyper M,Porter CBM,Ashenberg O,Waldman J,Drokhlyansky E,Wakiro I,Smillie C,Smith-Rosario G,Wu J,Dionne D,Vigneau S,Jané-Valbuena J,Tickle TL,Napolitano S,Su MJ,Patel AG,Karlstrom A,Gritsch S,Nomura M,Waghray A,Go

    更新日期:2020-05-01 00:00:00

  • HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy.

    abstract::Despite years of fully suppressive antiretroviral therapy (ART), HIV persists in its hosts and is never eradicated. One major barrier to eradication is that the virus infects multiple cell types that may individually contribute to HIV persistence. Tissue macrophages are critical contributors to HIV pathogenesis; howev...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.4319

    authors: Honeycutt JB,Thayer WO,Baker CE,Ribeiro RM,Lada SM,Cao Y,Cleary RA,Hudgens MG,Richman DD,Garcia JV

    更新日期:2017-05-01 00:00:00

  • Marked amelioration of established collagen-induced arthritis by treatment with antibodies to CD23 in vivo.

    abstract::CD23 is a low-affinity receptor for immunoglobulin E (IgE) expressed by a variety of haematopoietic cells. Proteolytic cleavage of the transmembrane receptor generates soluble forms, which can be detected in biological fluids. CD23 regulates many functional aspects of immune cells, both in its cell-associated and solu...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm0895-781

    authors: Plater-Zyberk C,Bonnefoy JY

    更新日期:1995-08-01 00:00:00

  • PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin.

    abstract::The N-terminal fragment of prolactin (16K PRL) inhibits tumor growth by impairing angiogenesis, but the underlying mechanisms are unknown. Here, we found that 16K PRL binds the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1), which is known to contextually promote tumor angiogenesis and growth. Loss o...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.3552

    authors: Bajou K,Herkenne S,Thijssen VL,D'Amico S,Nguyen NQ,Bouché A,Tabruyn S,Srahna M,Carabin JY,Nivelles O,Paques C,Cornelissen I,Lion M,Noel A,Gils A,Vinckier S,Declerck PJ,Griffioen AW,Dewerchin M,Martial JA,Carmeliet

    更新日期:2014-07-01 00:00:00

  • CD8+ T cell efficacy in vaccination and disease.

    abstract::Much effort has been devoted to the design of vaccines that induce adaptive cellular immunity, in particular CD8+ T cells, which have a central role in the host response to viral infections and cancers. To date, however, the development of effective T cell vaccines remains elusive. This is due, in part, to the lack of...

    journal_title:Nature medicine

    pub_type: 杂志文章,评审

    doi:10.1038/nm.f.1774

    authors: Appay V,Douek DC,Price DA

    更新日期:2008-06-01 00:00:00

  • Myocardial infarction accelerates breast cancer via innate immune reprogramming.

    abstract::Disruption of systemic homeostasis by either chronic or acute stressors, such as obesity1 or surgery2, alters cancer pathogenesis. Patients with cancer, particularly those with breast cancer, can be at increased risk of cardiovascular disease due to treatment toxicity and changes in lifestyle behaviors3-5. While eleva...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/s41591-020-0964-7

    authors: Koelwyn GJ,Newman AAC,Afonso MS,van Solingen C,Corr EM,Brown EJ,Albers KB,Yamaguchi N,Narke D,Schlegel M,Sharma M,Shanley LC,Barrett TJ,Rahman K,Mezzano V,Fisher EA,Park DS,Newman JD,Quail DF,Nelson ER,Caan BJ,J

    更新日期:2020-09-01 00:00:00

  • Durvalumab compared to maintenance chemotherapy in metastatic breast cancer: the randomized phase II SAFIR02-BREAST IMMUNO trial.

    abstract::The impact of single-agent antibodies against programmed death-ligand 1 (PD-L1) as maintenance therapy is unknown in patients with metastatic breast cancer. The SAFIR02-BREAST IMMUNO substudy included patients with human epidermal growth factor receptor type 2 (Her2)-negative metastatic breast cancer whose disease did...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/s41591-020-01189-2

    authors: Bachelot T,Filleron T,Bieche I,Arnedos M,Campone M,Dalenc F,Coussy F,Sablin MP,Debled M,Lefeuvre-Plesse C,Goncalves A,Reynier MM,Jacot W,You B,Barthelemy P,Verret B,Isambert N,Tchiknavorian X,Levy C,Thery JC,L'Har

    更新日期:2021-01-18 00:00:00

  • Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia.

    abstract::T-cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that most individuals with T-ALL carry activating mutations in the NOTCH1 gene. However, the signaling pathways and target genes responsible for Notch1-induced ne...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1524

    authors: Vilimas T,Mascarenhas J,Palomero T,Mandal M,Buonamici S,Meng F,Thompson B,Spaulding C,Macaroun S,Alegre ML,Kee BL,Ferrando A,Miele L,Aifantis I

    更新日期:2007-01-01 00:00:00

  • A link between diabetes and atherosclerosis: Glucose regulates expression of CD36 at the level of translation.

    abstract::Both the risk and the rate of development of atherosclerosis are increased in diabetics, but the mechanisms involved are unknown. Here we report a glucose-mediated increase in CD36 mRNA translation efficiency that results in increased expression of the macrophage scavenger receptor CD36. Expression of CD36 was increas...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/89969

    authors: Griffin E,Re A,Hamel N,Fu C,Bush H,McCaffrey T,Asch AS

    更新日期:2001-07-01 00:00:00

  • Antisense targeting of basic fibroblast growth factor and fibroblast growth factor receptor-1 in human melanomas blocks intratumoral angiogenesis and tumor growth.

    abstract::Unlike normal melanocytes, primary and metastatic human melanomas express high levels of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR-1) messenger RNA, and expression of these genes is essential in sustaining the proliferation of malignant melanomas in vitro. To determine whether...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm0897-887

    authors: Wang Y,Becker D

    更新日期:1997-08-01 00:00:00

  • Microbiota depletion promotes browning of white adipose tissue and reduces obesity.

    abstract::Brown adipose tissue (BAT) promotes a lean and healthy phenotype and improves insulin sensitivity. In response to cold or exercise, brown fat cells also emerge in the white adipose tissue (WAT; also known as beige cells), a process known as browning. Here we show that the development of functional beige fat in the ing...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.3994

    authors: Suárez-Zamorano N,Fabbiano S,Chevalier C,Stojanović O,Colin DJ,Stevanović A,Veyrat-Durebex C,Tarallo V,Rigo D,Germain S,Ilievska M,Montet X,Seimbille Y,Hapfelmeier S,Trajkovski M

    更新日期:2015-12-01 00:00:00

  • Anti-cancer activity of targeted pro-apoptotic peptides.

    abstract::We have designed short peptides composed of two functional domains, one a tumor blood vessel 'homing' motif and the other a programmed cell death-inducing sequence, and synthesized them by simple peptide chemistry. The 'homing' domain was designed to guide the peptide to targeted cells and allow its internalization. T...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/12469

    authors: Ellerby HM,Arap W,Ellerby LM,Kain R,Andrusiak R,Rio GD,Krajewski S,Lombardo CR,Rao R,Ruoslahti E,Bredesen DE,Pasqualini R

    更新日期:1999-09-01 00:00:00

  • TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity.

    abstract::We formulate a two-phase paradigm of autoimmunity associated with systemic lupus erythematosus, the archetypal autoimmune disease. The initial Toll-like receptor (TLR)-independent phase is mediated by dendritic cell uptake of apoptotic cell debris and associated nucleic acids, whereas the subsequent TLR-dependent phas...

    journal_title:Nature medicine

    pub_type: 杂志文章,评审

    doi:10.1038/nm1590

    authors: Baccala R,Hoebe K,Kono DH,Beutler B,Theofilopoulos AN

    更新日期:2007-05-01 00:00:00

  • Translational value of mouse models in oncology drug development.

    abstract::Much has been written about the advantages and disadvantages of various oncology model systems, with the overall finding that these models lack the predictive power required to translate preclinical efficacy into clinical activity. Despite assertions that some preclinical model systems are superior to others, no singl...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.3853

    authors: Gould SE,Junttila MR,de Sauvage FJ

    更新日期:2015-05-01 00:00:00

  • Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor.

    abstract::Natural inhibitors of angiogenesis are able to block pathological neovascularization without harming the preexisting vasculature. Here we show that two such inhibitors, thrombospondin-1 and pigment epithelium-derived factor, derive specificity for remodeling vessels from their dependence on Fas/Fas ligand (FasL)-media...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm0402-349

    authors: Volpert OV,Zaichuk T,Zhou W,Reiher F,Ferguson TA,Stuart PM,Amin M,Bouck NP

    更新日期:2002-04-01 00:00:00

  • Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice.

    abstract::The structure and function of blood vessels adapt to environmental changes such as physical development and exercise. This phenomenon is based on the ability of the endothelial cells to sense and respond to blood flow; however, the underlying mechanisms remain unclear. Here we show that the ATP-gated P2X4 ion channel,...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1338

    authors: Yamamoto K,Sokabe T,Matsumoto T,Yoshimura K,Shibata M,Ohura N,Fukuda T,Sato T,Sekine K,Kato S,Isshiki M,Fujita T,Kobayashi M,Kawamura K,Masuda H,Kamiya A,Ando J

    更新日期:2006-01-01 00:00:00

  • IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities.

    abstract::Sepsis remains a global clinical problem. By using the mouse cecal ligation and puncture model of sepsis, here we identify an important aspect of mast cell (MC)-dependent, innate immune defenses against Gram-negative bacteria by demonstrating that MC protease activity is regulated by interleukin-15 (IL-15). Mouse MCs ...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1615

    authors: Orinska Z,Maurer M,Mirghomizadeh F,Bulanova E,Metz M,Nashkevich N,Schiemann F,Schulmistrat J,Budagian V,Giron-Michel J,Brandt E,Paus R,Bulfone-Paus S

    更新日期:2007-08-01 00:00:00

  • An immunological epitope selective for pathological monomer-misfolded SOD1 in ALS.

    abstract::Misfolding of Cu/Zn-superoxide dismutase (SOD1) is emerging as a mechanism underlying motor neuron degeneration in individuals with amyotrophic lateral sclerosis (ALS) who carry a mutant SOD1 gene (SOD1 ALS). Here we describe a structure-guided approach to developing an antibody that specifically recognizes monomer-mi...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1559

    authors: Rakhit R,Robertson J,Vande Velde C,Horne P,Ruth DM,Griffin J,Cleveland DW,Cashman NR,Chakrabartty A

    更新日期:2007-06-01 00:00:00

  • Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells.

    abstract::We studied the effects of Lyn ablation on the survival of drug-resistant chronic myelogenous leukemia (CML) blast crisis cells using siRNA. Lyn siRNA reduced Lyn protein in both normal hematopoietic cells and BCR-ABL1-expressing (BCR-ABL1(+)) blasts by 80-95%. Within 48 h, siRNA-treated BCR-ABL1(+) blasts underwent ap...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1127

    authors: Ptasznik A,Nakata Y,Kalota A,Emerson SG,Gewirtz AM

    更新日期:2004-11-01 00:00:00

  • Emerging cytopathic and antigenic simian immunodeficiency virus variants influence AIDS progression.

    abstract::Genetic variants of human and simian immunodeficiency virus (HIV and SIV) that evolve during the course of infection and progression to AIDS are phenotypically and antigenically distinct from their progenitor viruses present at early stages of infection. However, it has been unclear how these late variants, which are ...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/8414

    authors: Kimata JT,Kuller L,Anderson DB,Dailey P,Overbaugh J

    更新日期:1999-05-01 00:00:00

  • Targeted therapy guided by single-cell transcriptomic analysis in drug-induced hypersensitivity syndrome: a case report.

    abstract::Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a potentially fatal multiorgan inflammatory disease associated with herpesvirus reactivation and subsequent onset of autoimmune diseases1-4. Pathophysiology remains elusive and therapeutic options are limited. ...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/s41591-019-0733-7

    authors: Kim D,Kobayashi T,Voisin B,Jo JH,Sakamoto K,Jin SP,Kelly M,Pasieka HB,Naff JL,Meyerle JH,Ikpeama ID,Fahle GA,Davis FP,Rosenzweig SD,Alejo JC,Pittaluga S,Kong HH,Freeman AF,Nagao K

    更新日期:2020-02-01 00:00:00

  • Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1.

    abstract::Hereditary hemochromatosis and transfusional iron overload are frequent clinical conditions associated with progressive iron accumulation in parenchymal tissues, leading to eventual organ failure. We have discovered a new mechanism to reverse iron overload-pharmacological modulation of the divalent metal transporter-1...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1542

    authors: Ludwiczek S,Theurl I,Muckenthaler MU,Jakab M,Mair SM,Theurl M,Kiss J,Paulmichl M,Hentze MW,Ritter M,Weiss G

    更新日期:2007-04-01 00:00:00

  • Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy.

    abstract::Ethylmalonic encephalopathy is caused by mutations in ETHE1, a mitochondrial matrix sulfur dioxygenase, leading to failure to detoxify sulfide, a product of intestinal anaerobes and, in trace amounts, tissues. Metronidazole, a bactericide, or N-acetylcysteine, a precursor of sulfide-buffering glutathione, substantiall...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm.2188

    authors: Viscomi C,Burlina AB,Dweikat I,Savoiardo M,Lamperti C,Hildebrandt T,Tiranti V,Zeviani M

    更新日期:2010-08-01 00:00:00

  • Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome.

    abstract::Hutchinson-Gilford progeria syndrome (HGPS) is a childhood premature aging disease caused by a spontaneous point mutation in lamin A (encoded by LMNA), one of the major architectural elements of the mammalian cell nucleus. The HGPS mutation activates an aberrant cryptic splice site in LMNA pre-mRNA, leading to synthes...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1204

    authors: Scaffidi P,Misteli T

    更新日期:2005-04-01 00:00:00

  • Graft-versus-host disease: suppression by statins.

    abstract::Two big challenges of transplantation biology are controlling the reaction of the graft to the host after hematopoietic stem cell transplantation and preventing rejection of donor organs by the host. Raewyn Broady and Megan K. Levings discuss the first challenge, examining studies suggesting that statins might be help...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1108-1155

    authors: Broady R,Levings MK

    更新日期:2008-11-01 00:00:00

  • Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia.

    abstract::Spinal sensorimotor networks that are functionally disconnected from the brain because of spinal cord injury (SCI) can be facilitated via epidural electrical stimulation (EES) to restore robust, coordinated motor activity in humans with paralysis1-3. Previously, we reported a clinical case of complete sensorimotor par...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/s41591-018-0175-7

    authors: Gill ML,Grahn PJ,Calvert JS,Linde MB,Lavrov IA,Strommen JA,Beck LA,Sayenko DG,Van Straaten MG,Drubach DI,Veith DD,Thoreson AR,Lopez C,Gerasimenko YP,Edgerton VR,Lee KH,Zhao KD

    更新日期:2018-11-01 00:00:00

  • Effects of underfeeding and oral vancomycin on gut microbiome and nutrient absorption in humans.

    abstract::Direct evidence in humans for the impact of the microbiome on nutrient absorption is lacking. We conducted an extended inpatient study using two interventions that we hypothesized would alter the gut microbiome and nutrient absorption. In each, stool calorie loss, a direct proxy of nutrient absorption, was measured. T...

    journal_title:Nature medicine

    pub_type: 杂志文章,随机对照试验

    doi:10.1038/s41591-020-0801-z

    authors: Basolo A,Hohenadel M,Ang QY,Piaggi P,Heinitz S,Walter M,Walter P,Parrington S,Trinidad DD,von Schwartzenberg RJ,Turnbaugh PJ,Krakoff J

    更新日期:2020-04-01 00:00:00

  • Simultaneous PET-MRI: a new approach for functional and morphological imaging.

    abstract::Noninvasive imaging at the molecular level is an emerging field in biomedical research. This paper introduces a new technology synergizing two leading imaging methodologies: positron emission tomography (PET) and magnetic resonance imaging (MRI). Although the value of PET lies in its high-sensitivity tracking of bioma...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1700

    authors: Judenhofer MS,Wehrl HF,Newport DF,Catana C,Siegel SB,Becker M,Thielscher A,Kneilling M,Lichy MP,Eichner M,Klingel K,Reischl G,Widmaier S,Röcken M,Nutt RE,Machulla HJ,Uludag K,Cherry SR,Claussen CD,Pichler BJ

    更新日期:2008-04-01 00:00:00

  • Dok1 mediates high-fat diet-induced adipocyte hypertrophy and obesity through modulation of PPAR-gamma phosphorylation.

    abstract::Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin, but other substrates of the insulin receptor kinase, such as Gab1, c-Cbl, SH2-B and APS, are also of physiological relevance. Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapt...

    journal_title:Nature medicine

    pub_type: 杂志文章

    doi:10.1038/nm1706

    authors: Hosooka T,Noguchi T,Kotani K,Nakamura T,Sakaue H,Inoue H,Ogawa W,Tobimatsu K,Takazawa K,Sakai M,Matsuki Y,Hiramatsu R,Yasuda T,Lazar MA,Yamanashi Y,Kasuga M

    更新日期:2008-02-01 00:00:00