Evidence map›Paper›PMID 30670779›Full record

ArticleOncogene2019

A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction.

Klaartje Somers, Victoria W Wen, Shiloh M C Middlemiss, Brenna Osborne, Helen Forgham, MoonSun Jung, Mawar Karsa, Molly Clifton, Angelika Bongers, Jixuan Gao and 27 more

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

Article in Oncogene, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
1.2field-weighted citation impact, top 22% 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

11 citing papers in PubMed, 30 citations in OpenAlex.

  1. Review
  2. Review
  3. Article
  4. FDA-approved disulfiram as a novel treatment for aggressive leukemia.Journal of molecular medicine (Berlin, Germany) · 2024
    Article
  5. Article
  6. Article
  7. Review
  8. Article
  9. SystematicFrontiers in oncology · 2021
    Article
  10. Article
  11. Oncogenic and tumor suppressor function of MEIS and associated factors.Turkish journal of biology = Turk biyoloji dergisi · 2020
    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

37 authors at 10 institutions in 5 countries.

Klaartje SomersChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Victoria W WenChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Shiloh M C MiddlemissChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Brenna OsborneMitochondrial Bioenergetics Laboratory, School of Medical Sciences, UNSW, Randwick, NSW, Australia.ORCID http://orcid.org/0000-0002-0197-3010
Helen ForghamChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
MoonSun JungChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Mawar KarsaChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Molly CliftonChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Angelika BongersChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Jixuan GaoChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Chelsea MayohChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Newsha Raoufi-RadChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Eric P KusnadiPeter MacCallum Cancer Centre, Melbourne, VIC, Australia.
Kate M HannanThe John Curtin School of Medical Research, The Australian National University, Canberra City, ACT, Australia.
David A ScottSanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
Alan KwekChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Bing LiuChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Claudia FlemmingChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Daria A ChudakovaChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Ruby PandherChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Tim W FailesChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
James LimChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Andrea AngeliNeurofarba Department, University of Florence, Florence, Italy.
Andrei L OstermanSanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
Toshihiko ImamuraDepartment of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Ursula R KeesTelethon Kids Institute, University of Western Australia, Perth, WA, Australia.
Claudiu T SupuranNeurofarba Department, University of Florence, Florence, Italy.
Richard B PearsonPeter MacCallum Cancer Centre, Melbourne, VIC, Australia.ORCID http://orcid.org/0000-0001-5919-5090
Ross D HannanThe John Curtin School of Medical Research, The Australian National University, Canberra City, ACT, Australia.ORCID http://orcid.org/0000-0002-2166-4493
Thomas P DavisARC Centre of Excellence in Convergent Bio-Nano Science and Technology Monash Institute of Pharmaceutical Sciences, Monash University, Clayton, VIC, Australia.ORCID http://orcid.org/0000-0003-2581-4986
Joshua McCarrollChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Maria KavallarisChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.ORCID http://orcid.org/0000-0003-2309-898X
Nigel TurnerMitochondrial Bioenergetics Laboratory, School of Medical Sciences, UNSW, Randwick, NSW, Australia.
Andrei V GudkovDepartment of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
Michelle HaberChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Murray D NorrisChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia.
Michelle J HendersonChildren's Cancer Institute, Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia. mhenderson@ccia.unsw.edu.au.
Children's Cancer Institute Australia · AUAustralian National University · AUPeter MacCallum Cancer Centre · AUSanford Burnham Prebys Medical Discovery Institute · USUniversity of Florence · ITCancer Institute of New South Wales · AUKyoto Prefectural University of Medicine · JPRoswell Park Comprehensive Cancer Center · USThe Kids Research Institute Australia · AUUniversity of Warwick · GB

Funding

Tumor Microenvironment and Cancer ImmunologyP30CA030199 · NCI · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI ELENA B PASQUALE · 1985 to 2026
$107.2M
NCI NIH HHS P30 CA030199
6 · The paper itself

Abstract

Survival rates for pediatric patients suffering from mixed lineage leukemia (MLL)-rearranged leukemia remain below 50% and more targeted, less toxic therapies are urgently needed. A screening method optimized to discover cytotoxic compounds selective for MLL-rearranged leukemia identified CCI-006 as a novel inhibitor of MLL-rearranged and CALM-AF10 translocated leukemias that share common leukemogenic pathways. CCI-006 inhibited mitochondrial respiration and induced mitochondrial membrane depolarization and apoptosis in a subset (7/11, 64%) of MLL-rearranged leukemia cell lines within a few hours of treatment. The unresponsive MLL-rearranged leukemia cells did not undergo mitochondrial membrane depolarization or apoptosis despite a similar attenuation of mitochondrial respiration by the compound. In comparison to the sensitive cells, the unresponsive MLL-rearranged leukemia cells were characterized by a more glycolytic metabolic phenotype, exemplified by a more pronounced sensitivity to glycolysis inhibitors and elevated HIF1α expression. Silencing of HIF1α expression sensitized an intrinsically unresponsive MLL-rearranged leukemia cell to CCI-006, indicating that this pathway plays a role in determining sensitivity to the compound. In addition, unresponsive MLL-rearranged leukemia cells expressed increased levels of MEIS1, an important leukemogenic MLL target gene that plays a role in regulating metabolic phenotype through HIF1α. MEIS1 expression was also variable in a pediatric MLL-rearranged ALL patient dataset, highlighting the existence of a previously undescribed metabolic variability in MLL-rearranged leukemia that may contribute to the heterogeneity of the disease. This study thus identified a novel small molecule that rapidly kills MLL-rearranged leukemia cells by targeting a metabolic vulnerability in a subset of low HIF1α/low MEIS1-expressing MLL-rearranged leukemia cells.

Indexed as

AcrylatesAnimalsAntineoplastic AgentsCell Line, TumorDrug Resistance, NeoplasmFuransGene Expression Regulation, LeukemicGene RearrangementHistone-Lysine N-MethyltransferaseHumansHypoxia-Inducible Factor 1, alpha SubunitLeukemia, Myeloid, AcuteMice, Inbred StrainsMitochondriaMyeloid Ecotropic Viral Integration Site 1 ProteinMyeloid-Lymphoid Leukemia ProteinAcrylatesAntineoplastic AgentsFuransHIF1A protein, humanHistone-Lysine N-MethyltransferaseHypoxia-Inducible Factor 1, alpha SubunitKMT2A protein, humanMEIS1 protein, humanMyeloid Ecotropic Viral Integration Site 1 ProteinMyeloid-Lymphoid Leukemia ProteinNitriles

Identifiers

PMID30670779
PMCPMC6756102
OpenAlexW2914247892

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.