Evidence map›Paper›PMID 27181063›Full record

ArticleExperimental hematology2016

Comprehensive genomic analysis reveals FLT3 activation and a therapeutic strategy for a patient with relapsed adult B-lymphoblastic leukemia.

Malachi Griffith, Obi L Griffith, Kilannin Krysiak, Zachary L Skidmore, Matthew J Christopher, Jeffery M Klco, Avinash Ramu, Tamara L Lamprecht, Alex H Wagner, Katie M Campbell and 27 more

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

Article in Experimental hematology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.

0numbers the graph read from it
0cells of the map it votes in
35citing papers in PubMed
6.1field-weighted citation impact, top 3% 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

35 citing papers in PubMed, 56 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

37 authors at 4 institutions in 1 country.

Malachi GriffithMcDonnell Genome Institute, Washington University, St. Louis, MO, USA; Department of Genetics, Washington University, St. Louis, MO, USA; Siteman Cancer Center, Washington University, St. Louis, MO, USA. Electronic address: mgriffit@wustl.edu.
Obi L GriffithMcDonnell Genome Institute, Washington University, St. Louis, MO, USA; Department of Genetics, Washington University, St. Louis, MO, USA; Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
Kilannin KrysiakMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Zachary L SkidmoreMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Matthew J ChristopherDepartment of Medicine, Washington University, St. Louis, MO, USA.
Jeffery M KlcoDepartment of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Avinash RamuMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Tamara L LamprechtDepartment of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Alex H WagnerMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Katie M CampbellMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Robert LesurfMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Jasreet HundalMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Jin ZhangMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Nicholas C SpiesMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Benjamin J AinscoughMcDonnell Genome Institute, Washington University, St. Louis, MO, USA; Siteman Cancer Center, Washington University, St. Louis, MO, USA.
David E LarsonMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Sharon E HeathDepartment of Medicine, Washington University, St. Louis, MO, USA.
Catrina FronickMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Shelly O'LaughlinMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Robert S FultonMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Vincent MagriniMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Sean McGrathMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Scott M SmithMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Christopher A MillerMcDonnell Genome Institute, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
Christopher A MaherMcDonnell Genome Institute, Washington University, St. Louis, MO, USA; Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA; Department of Biomedical Engineering, Washington University, St. Louis, MO, USA.
Jacqueline E PaytonSiteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA; Department of Pathology, Washington University, St. Louis, MO, USA.
Jason R WalkerMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
James M EldredMcDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Matthew J WalterSiteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
Daniel C LinkSiteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
Timothy A GraubertMassachusetts General Hospital Cancer Center, Boston, MA, USA.
Peter WesterveltSiteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
Shashikant KulkarniDepartment of Pathology, Washington University, St. Louis, MO, USA.
John F DiPersioSiteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
Elaine R MardisMcDonnell Genome Institute, Washington University, St. Louis, MO, USA; Department of Genetics, Washington University, St. Louis, MO, USA; Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
Richard K WilsonMcDonnell Genome Institute, Washington University, St. Louis, MO, USA; Department of Genetics, Washington University, St. Louis, MO, USA; Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA.
Timothy J LeyMcDonnell Genome Institute, Washington University, St. Louis, MO, USA; Department of Genetics, Washington University, St. Louis, MO, USA; Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Medicine, Washington University, St. Louis, MO, USA. Electronic address: timley@wustl.edu.
James S. McDonnell Foundation · USWashington University in St. Louis · USSt. Jude Children's Research Hospital · USMassachusetts General Hospital · US

Funding

Large Scale Genome SequencingU54HG003079 · NHGRI · WASHINGTON UNIVERSITY · PI DUTCHER, SUSAN K · 2004 to 2016
$445.7M
Washington University Center for Cellular ImagingP30CA091842 · NCI · WASHINGTON UNIVERSITY · PI TIMOTHY J. EBERLEIN · 2001 to 2026
$128.0M
Specimen Acquistition and Expression ProfilingP01CA101937 · NCI · WASHINGTON UNIVERSITY · PI LEY, TIMOTHY J. · 2003 to 2023
$58.8M
Molecular Pathogenesis of Acute Myeloid LeukemiaR35CA197561 · NCI · WASHINGTON UNIVERSITY · PI Timothy J. Ley · 2015 to 2026
$11.0M
MOLECULAR ONCOLOGY TRAINING GRANTT32CA113275 · NCI · WASHINGTON UNIVERSITY · PI Matthew J Walter · 2006 to 2026
$5.7M
Integrated Analysis & Interpretation of Whole Genome Exome & Transcriptome SequenR00HG007940 · NHGRI · WASHINGTON UNIVERSITY · PI GRIFFITH, MALACHI · 2017 to 2019
$724k
Characterization of Cancer Transcriptomes using Next Generation SequencingR00CA149182 · NCI · WASHINGTON UNIVERSITY · PI MAHER, CHRISTOPHER A · 2011 to 2013
$685k
DEFINING THE REGULATORY, NON-CODING, MUTATIONAL LANDSCAPE OF BREAST CANCERK22CA188163 · NCI · WASHINGTON UNIVERSITY · PI GRIFFITH, OBI L. · 2014 to 2016
$515k
CLONAL EVOLUTION OF STRUCTURAL VARIANTS IN THE PROGRESSION OF METASTATIC COLORECTR21CA185983 · NCI · WASHINGTON UNIVERSITY · PI MAHER, CHRISTOPHER A · 2014 to 2015
$315k
INTEGRATED ANALYSIS & INTERPRETATION OF WHOLE GENOME, EXOME & TRANSCRIPTOME SEQUENCE DATA IN CANCERK99HG007940 · NHGRI · WASHINGTON UNIVERSITY · PI GRIFFITH, MALACHI · 2015 to 2016
$264k
NCI NIH HHS K22 CA188163NCI NIH HHS P01 CA101937NCI NIH HHS P30 CA091842NCI NIH HHS R00 CA149182NCI NIH HHS R21 CA185983NCI NIH HHS R35 CA197561NCI NIH HHS T32 CA113275NHGRI NIH HHS K99 HG007940NHGRI NIH HHS R00 HG007940NHGRI NIH HHS U54 HG003079
6 · The paper itself

Abstract

The genomic events responsible for the pathogenesis of relapsed adult B-lymphoblastic leukemia (B-ALL) are not yet clear. We performed integrative analysis of whole-genome, whole-exome, custom capture, whole-transcriptome (RNA-seq), and locus-specific genomic assays across nine time points from a patient with primary de novo B-ALL. Comprehensive genome and transcriptome characterization revealed a dramatic tumor evolution during progression, yielding a tumor with complex clonal architecture at second relapse. We observed and validated point mutations in EP300 and NF1, a highly expressed EP300-ZNF384 gene fusion, a microdeletion in IKZF1, a focal deletion affecting SETD2, and large deletions affecting RB1, PAX5, NF1, and ETV6. Although the genome analysis revealed events of potential biological relevance, no clinically actionable treatment options were evident at the time of the second relapse. However, transcriptome analysis identified aberrant overexpression of the targetable protein kinase encoded by the FLT3 gene. Although the patient had refractory disease after salvage therapy for the second relapse, treatment with the FLT3 inhibitor sunitinib rapidly induced a near complete molecular response, permitting the patient to proceed to a matched-unrelated donor stem cell transplantation. The patient remains in complete remission more than 4 years later. Analysis of this patient's relapse genome revealed an unexpected, actionable therapeutic target that led to a specific therapy associated with a rapid clinical response. For some patients with relapsed or refractory cancers, this approach may indicate a novel therapeutic intervention that could alter outcome.

Indexed as

GenomicsTranscriptional ActivationAdultAntineoplastic Combined Chemotherapy ProtocolsBiopsyBone MarrowBone Marrow TransplantationCyclophosphamideCytogenetic AnalysisDexamethasoneDoxorubicinFlow Cytometryfms-Like Tyrosine Kinase 3Gene Expression ProfilingGenetic VariationGraft vs Host DiseaseCyclophosphamideDexamethasoneDoxorubicinFLT3 protein, humanfms-Like Tyrosine Kinase 3Vincristine

Identifiers

PMID27181063
PMCPMC4914477
OpenAlexW2350389426

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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.