Evidence map›Paper›PMID 25650089›Full record

ArticleLeukemia2015

Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition.

L Chen, W Chen, M Mysliwski, J Serio, J Ropa, F A Abulwerdi, R J Chan, J P Patel, M S Tallman, E Paietta and 5 more

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

Article in Leukemia, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.

0numbers the graph read from it
0cells of the map it votes in
44citing papers in PubMed
2.4field-weighted citation impact, top 11% 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

44 citing papers in PubMed, 64 citations in OpenAlex.

  1. Article
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  8. Cancers · 2024
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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

15 authors at 5 institutions in 1 country.

L Chen1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
W Chen1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
M Mysliwski1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
J Serio1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
J Ropa1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
F A Abulwerdi1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Interdepartmental Program in Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
R J Chan1] Herman B Wells Center for Pediatric Research, Department of Medical and Molecular Genetics, University School of Medicine, Indianapolis, IN, USA [2] Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
J P PatelHuman Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
M S TallmanHuman Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
E PaiettaMontefiore Medical Center-North Division, Immunology Laboratory, Cancer Center, Bronx, NY, USA.
A Melnick1] Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA [2] Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA.
R L LevineHuman Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
O Abdel-WahabHuman Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Z Nikolovska-Coleska1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
A G Muntean1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
University of Michigan–Ann Arbor · USMemorial Sloan Kettering Cancer Center · USCornell University · USIndiana University – Purdue University Indianapolis · USMontefiore Medical Center · US

Funding

XenograftP30CA046592 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Alexey I Nesvizhskii · 1988 to 2026
$178.2M
Project-006U10CA180820 · NCI · ECOG-ACRIN MEDICAL RESEARCH FOUNDATION · PI Peter J ODwyer · 2014 to 2026
$167.6M
ECOG OPERATIONS OFFICE (IBCSG)U10CA021115 · NCI · UNIVERSITY OF WISCONSIN MADISON · PI COMIS, ROBERT L · 1985 to 2013
$132.6M
ECOG-ACRIN Biospecimen Bank to Support NCTNU24CA196172 · NCI · ECOG-ACRIN MEDICAL RESEARCH FOUNDATION · PI STANLEY R. HAMILTON, Scott D Jewell · 2015 to 2026
$41.1M
ECOG Specimen BankingU24CA114737 · NCI · FRONTIER SCI &TECHNOLOGY RSCH FDN, INC · PI COMIS, ROBERT L · 2005 to 2014
$9.3M
Role of Shp2 in FLT3-ITD-Induced LeukemogenesisR01CA134777 · NCI · INDIANA UNIVERSITY INDIANAPOLIS · PI KAPUR, REUBEN · 2011 to 2023
$3.4M
ECOG-ACRIN INTEGRATED LEUKEMIA TRANSLATIONAL RESEARCH CENTERU10CA180827 · NCI · MONTEFIORE MEDICAL CENTER (BRONX, NY) · PI LEVINE, ROSS L, MELNICK, ARI M. · 2014 to 2018
$3.0M
Novel selective small-molecule inhibitors of Mcl-1 proteinR01CA149442 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI NIKOLOVSKA-COLESKA, ZANETA · 2010 to 2014
$1.5M
Post-translational regulation of MLL in leukemogenesisR00CA158136 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI MUNTEAN, ANDREW GEORGE · 2012 to 2014
$670k
NCI NIH HHS P30 CA046592NCI NIH HHS R00 CA158136NCI NIH HHS R01 CA134777NCI NIH HHS R01 CA149442NCI NIH HHS R01-CA149442NCI NIH HHS U10 CA021115NCI NIH HHS U10 CA180820NCI NIH HHS U10 CA180827NCI NIH HHS U24 CA114737NCI NIH HHS U24 CA196172
6 · The paper itself

Abstract

PTPN11 encodes the Shp2 non-receptor protein-tyrosine phosphatase implicated in several signaling pathways. Activating mutations in Shp2 are commonly associated with juvenile myelomonocytic leukemia but are not as well defined in other neoplasms. Here we report that Shp2 mutations occur in human acute myeloid leukemia (AML) at a rate of 6.6% (6/91) in the ECOG E1900 data set. We examined the role of mutated Shp2 in leukemias harboring MLL translocations, which co-occur in human AML. The hyperactive Shp2E76K mutant, commonly observed in leukemia patients, significantly accelerated MLL-AF9-mediated leukemogenesis in vivo. Shp2E76K increased leukemic stem cell frequency and affords MLL-AF9 leukemic cells IL3 cytokine hypersensitivity. As Shp2 is reported to regulate anti-apoptotic genes, we investigated Bcl2, Bcl-xL and Mcl1 expression in MLL-AF9 leukemic cells with and without Shp2E76K. Although the Bcl2 family of genes was upregulated in Shp2E76K cells, Mcl1 showed the highest upregulation in MLL-AF9 cells in response to Shp2E76K. Indeed, expression of Mcl1 in MLL-AF9 cells phenocopies expression of Shp2E76K, suggesting Shp2 mutations cooperate through activation of anti-apoptotic genes. Finally, we show Shp2E76K mutations reduce sensitivity of AML cells to small-molecule-mediated Mcl1 inhibition, suggesting reduced efficacy of drugs targeting MCL1 in patients with hyperactive Shp2.

Indexed as

AnimalsApoptosisApoptosis Regulatory ProteinsBlotting, WesternCell ProliferationClinical Trials, Phase III as TopicDrug Resistance, NeoplasmFemaleHumansInterleukin-3Leukemia, Myeloid, AcuteMiceMice, Inbred C57BLMutationMyeloid Cell Leukemia Sequence 1 ProteinNeoplastic Stem CellsApoptosis Regulatory ProteinsInterleukin-3Mcl1 protein, mouseMLL-AF9 fusion protein, mouseMyeloid Cell Leukemia Sequence 1 ProteinOncogene Proteins, FusionProtein Tyrosine Phosphatase, Non-Receptor Type 11PTPN11 protein, humanPtpn11 protein, mouseRNA, MessengerRNA, Small Interfering

Identifiers

PMID25650089
PMCPMC4456293
OpenAlexW2066932792

What OpenQuestion holds

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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.