Evidence map›Paper›PMID 27991934›Full record

ArticleOncogene2017

Ras oncogene-independent activation of RALB signaling is a targetable mechanism of escape from NRAS(V12) oncogene addiction in acute myeloid leukemia.

E J Pomeroy, L A Lee, R D W Lee, D K Schirm, N A Temiz, J Ma, T A Gruber, E Diaz-Flores, B S Moriarity, J R Downing and 3 more

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

Article in Oncogene, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
0.7field-weighted citation impact, top 25% 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

7 citing papers in PubMed, 11 citations in OpenAlex.

  1. Review
  2. Review
  3. Article
  4. Review
  5. Article
  6. [Advances in the mouse models of myeloid leukemia].Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi · 2019
    Review
  7. Article
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

13 authors at 4 institutions in 1 country.

E J PomeroyDepartment of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN, USA.
L A LeeDepartment of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN, USA.
R D W LeeDepartment of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN, USA.
D K SchirmDepartment of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN, USA.
N A TemizMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
J MaDepartment of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
T A GruberDepartment of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
E Diaz-FloresDepartment of Pediatrics, University of California, San Francisco, CA, USA.
B S MoriarityMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
J R DowningDepartment of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
K M ShannonDepartment of Pediatrics, University of California, San Francisco, CA, USA.
D A LargaespadaMasonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
C E EckfeldtDepartment of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN, USA.
University of Minnesota Medical Center · USSt. Jude Children's Research Hospital · USUniversity of California, San Francisco · USMinnesota Oncology · US

Funding

Women's CancerP30CA077598 · NCI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI Jeffrey S. Miller · 1998 to 2026
$100.4M
TRAINING IN HEMOGLOBIN &CELL MEMBRANE RESEARCHT32HL007062 · NHLBI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI Jeffrey S. Miller, Gregory M Vercellotti · 1985 to 2026
$10.3M
NCI NIH HHS P30 CA077598NHLBI NIH HHS T32 HL007062
6 · The paper itself

Abstract

Somatic mutations that lead to constitutive activation of NRAS and KRAS proto-oncogenes are among the most common in human cancer and frequently occur in acute myeloid leukemia (AML). An inducible NRAS(V12)-driven AML mouse model has established a critical role for continued NRAS(V12) expression in leukemia maintenance. In this model genetic suppression of NRAS(V12) expression results in rapid leukemia remission, but some mice undergo spontaneous relapse with NRAS(V12)-independent (NRI) AMLs providing an opportunity to identify mechanisms that bypass the requirement for Ras oncogene activity and drive leukemia relapse. We found that relapsed NRI AMLs are devoid of NRAS(V12) expression and signaling through the major oncogenic Ras effector pathways, phosphatidylinositol-3-kinase and mitogen-activated protein kinase, but express higher levels of an alternate Ras effector, Ralb, and exhibit NRI phosphorylation of the RALB effector TBK1, implicating RALB signaling in AML relapse. Functional studies confirmed that inhibiting CDK5-mediated RALB activation with a clinically relevant experimental drug, dinaciclib, led to potent RALB-dependent antileukemic effects in human AML cell lines, induced apoptosis in patient-derived AML samples in vitro and led to a 2-log reduction in the leukemic burden in patient-derived xenograft mice. Furthermore, dinaciclib potently suppressed the clonogenic potential of relapsed NRI AMLs in vitro and prevented the development of relapsed AML in vivo. Our findings demonstrate that Ras oncogene-independent activation of RALB signaling is a therapeutically targetable mechanism of escape from NRAS oncogene addiction in AML.

Indexed as

Gene Expression Regulation, NeoplasticAnimalsApoptosisBiomarkers, TumorCell ProliferationFemaleGTP PhosphohydrolasesHumansLeukemia, ExperimentalLeukemia, Myeloid, AcuteMaleMembrane ProteinsMiceMice, SCIDMitogen-Activated Protein KinasesMonomeric GTP-Binding ProteinsBiomarkers, TumorGTP PhosphohydrolasesMembrane ProteinsMitogen-Activated Protein KinasesMonomeric GTP-Binding ProteinsNRAS protein, humanRalb protein, humanral GTP-Binding Proteins

Identifiers

PMID27991934
PMCPMC5464975
OpenAlexW2566610347

What OpenQuestion holds

Textmetadata
LicenceCC BY
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.