Evidence map›Paper›PMID 27641501›Full record

ArticleCell2016

Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia.

David B Sykes, Youmna S Kfoury, François E Mercier, Mathias J Wawer, Jason M Law, Mark K Haynes, Timothy A Lewis, Amir Schajnovitz, Esha Jain, Dongjun Lee and 20 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 302 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
302citing papers in PubMed, 1 pooled it
19.0field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

302 citing papers in PubMed, 1 synthesis or guideline pooled it, 476 citations in OpenAlex.

  1. Pooled it
  2. Article
  3. Article
  4. Article
  5. Article
  6. Article
  7. Article
  8. Article
  9. Review
  10. Article
  11. Review
  12. Article
  13. Article
  14. Article
  15. Article
  16. Article
  17. Article
  18. Article
  19. Article
  20. Article

242 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

30 authors at 7 institutions in 2 countries.

David B SykesCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: dbsykes@mgh.harvard.edu.
Youmna S KfouryCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
François E MercierCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Mathias J WawerCenter for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jason M LawCenter for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Mark K HaynesCenter for Molecular Discovery, University of New Mexico, Albuquerque, NM 87131, USA.
Timothy A LewisCenter for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
Amir SchajnovitzCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Esha JainCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Dongjun LeeCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Hanna MeyerBayer Pharma AG, Berlin 13353, Germany.
Kerry A PierceMetabolite Profiling Platform, Broad Institute, Cambridge, MA 02142, USA.
Nicola J TollidayCenter for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Anna WallerCenter for Molecular Discovery, University of New Mexico, Albuquerque, NM 87131, USA.
Steven J FerraraCenter for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Ashley L EheimBayer Pharma AG, Berlin 13353, Germany.
Detlef StoeckigtBayer Pharma AG, Berlin 13353, Germany.
Katrina L MaxcyCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Julien M CobertCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Jacqueline BachandCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Brian A SzekelyCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Siddhartha MukherjeeIrving Cancer Research Center, Columbia University School of Medicine, New York, NY 10032, USA.
Larry A SklarCenter for Molecular Discovery, University of New Mexico, Albuquerque, NM 87131, USA.
Joanne D KotzCenter for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
Clary B ClishMetabolite Profiling Platform, Broad Institute, Cambridge, MA 02142, USA.
Ruslan I SadreyevDepartment of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Paul A ClemonsCenter for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA.
Andreas JanzerBayer Pharma AG, Berlin 13353, Germany.
Stuart L SchreiberCenter for the Science of Therapeutics, Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Cambridge, MA 02138, USA.
David T ScaddenCenter for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: dscadden@mgh.harvard.edu.
Broad Institute · USMassachusetts General Hospital · USBayer (Germany) · DEHarvard University · USUniversity of New Mexico · USColumbia University · USHarvard Stem Cell Institute · US

Funding

User Driven ProjectU54HG005032 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI SCHREIBER, STUART L · 2008 to 2013
$88.1M
Yeast Biology ConsortiumU54MH084690 · NIMH · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · PI TEGOS, GEORGE P · 2008 to 2013
$14.4M
Developing differentiation therapy for the treatment of patients with acute myeloid leukemiaK08CA201640 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI SYKES, DAVID B · 2017 to 2020
$677k
ImageStream X Analyzer 2011S10OD012027 · OD · MASSACHUSETTS GENERAL HOSPITAL · PI PREFFER, FREDERIC IRA · 2012 to 2012
$595k
Discovering small molecules that overcome differentiation arrest in acute myeloidR03DA032471 · NIDA · MASSACHUSETTS GENERAL HOSPITAL · PI SYKES, DAVID B · 2011 to 2012
$88k
NCI NIH HHS K08 CA201640NHGRI NIH HHS U54 HG005032NIDA NIH HHS R03 DA032471NIH HHS S10 OD012027NIMH NIH HHS U54 MH084690
6 · The paper itself

Abstract

While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML.

Indexed as

Molecular Targeted TherapyAnimalsAntineoplastic AgentsCell DifferentiationDihydroorotate DehydrogenaseEnzyme InhibitorsHigh-Throughput Screening AssaysHomeodomain ProteinsHumansLeukemia, Myeloid, AcuteMiceMyeloid CellsOxidoreductases Acting on CH-CH Group DonorsPyrimidinesSmall Molecule LibrariesXenograft Model Antitumor AssaysAntineoplastic AgentsDihydroorotate DehydrogenaseEnzyme Inhibitorshomeobox protein HOXA9Homeodomain ProteinsOxidoreductases Acting on CH-CH Group DonorspyrimidinePyrimidinesSmall Molecule Librariesacute myeloid leukemiabrequinardifferentiationdihydroorotate dehydrogenasehigh-throughput screenHoxA9leukemia-initiating cellmetabolic inhibitorphenotypic screen

Identifiers

PMID27641501
PMCPMC7360335
OpenAlexW2520159331

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.