Evidence map›Paper›PMID 37088806›Full record

ArticleBlood cancer journal2023

Combined inhibition of BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance of TP53-mutant acute myeloid leukemia to individual BH3 mimetics.

Bing Z Carter, Po Yee Mak, Wenjing Tao, Edward Ayoub, Lauren B Ostermann, Xuelin Huang, Sanam Loghavi, Steffen Boettcher, Yuki Nishida, Vivian Ruvolo and 6 more

Erratum issuedOpen access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Blood cancer journal, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 20 papers.

0numbers the graph read from it
0cells of the map it votes in
20citing papers in PubMed
8.1field-weighted citation impact, top 2% 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

20 citing papers in PubMed, 29 citations in OpenAlex.

  1. Review
  2. Article
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  4. Pandora's Box of AML: HowBiomedicines · 2025
    Review
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  7. Review
  8. bioRxiv : the preprint server for biology · 2025
    Article
  9. Review
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  15. Article
  16. Mitochondria and Acute Leukemia: A Clinician's Perspective.International journal of molecular sciences · 2024
    Review
  17. Article
  18. Review
  19. Review
  20. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

16 authors at 4 institutions in 3 countries.

Bing Z CarterSection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. bicarter@mdanderson.org.ORCID http://orcid.org/0000-0003-0076-0889
Po Yee MakSection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Wenjing TaoSection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Edward AyoubSection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Lauren B OstermannSection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID http://orcid.org/0000-0002-3330-2174
Xuelin HuangDepartment of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Sanam LoghaviDepartment of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID http://orcid.org/0000-0001-8980-3202
Steffen BoettcherDepartment of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.ORCID http://orcid.org/0000-0001-9937-0957
Yuki NishidaSection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Vivian RuvoloSection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Paul E HughesOncology Research, Amgen Inc, Thousand Oaks, CA, USA.
Phuong K MorrowAmgen Inc, Thousand Oaks, CA, USA.
Torsten HaferlachMLL Munich Leukemia Laboratory, Munich, Germany.ORCID http://orcid.org/0000-0003-0196-2837
Steven KornblauSection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID http://orcid.org/0000-0002-5990-9548
Muharrem MuftuogluSection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Michael AndreeffSection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. mandreef@mdanderson.org.ORCID http://orcid.org/0000-0002-1144-1958
The University of Texas MD Anderson Cancer Center · USAmgen (United States) · USMunich Leukemia Laboratory (Germany) · DEUniversity of Zurich · CH

Funding

Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Fabien Delerue · 1985 to 2026
$290.8M
Targeting Quiescence Pathways to Overcome Chemoresistance in EVI1-Overexpressing LeukemiaF32CA271697 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI AYOUB, EDWARD · 2022 to 2024
$226k
NCI NIH HHS F32 CA271697NCI NIH HHS P30 CA016672
6 · The paper itself

Abstract

TP53-mutant acute myeloid leukemia (AML) respond poorly to currently available treatments, including venetoclax-based drug combinations and pose a major therapeutic challenge. Analyses of RNA sequencing and reverse phase protein array datasets revealed significantly lower BAX RNA and protein levels in TP53-mutant compared to TP53-wild-type (WT) AML, a finding confirmed in isogenic CRISPR-generated TP53-knockout and -mutant AML. The response to either BCL-2 (venetoclax) or MCL-1 (AMG176) inhibition was BAX-dependent and much reduced in TP53-mutant compared to TP53-WT cells, while the combination of two BH3 mimetics effectively activated BAX, circumventing survival mechanisms in cells treated with either BH3 mimetic, and synergistically induced cell death in TP53-mutant AML and stem/progenitor cells. The BH3 mimetic-driven stress response and cell death patterns after dual inhibition were largely independent of TP53 status and affected by apoptosis induction. Co-targeting, but not individual targeting of BCL-2 and MCL-1 in mice xenografted with TP53-WT and TP53-R248W Molm13 cells suppressed both TP53-WT and TP53-mutant cell growth and significantly prolonged survival. Our results demonstrate that co-targeting BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance to individual BH3 mimetics in TP53-mutant cells, thus shifting cell fate from survival to death in TP53-deficient and -mutant AML. This concept warrants clinical evaluation.

Indexed as

Antineoplastic AgentsLeukemia, Myeloid, AcuteAnimalsApoptosisbcl-2-Associated X ProteinBridged Bicyclo Compounds, HeterocyclicCell Line, TumorMiceMyeloid Cell Leukemia Sequence 1 ProteinNaphthalenesProto-Oncogene Proteins c-bcl-2Spiro CompoundsSulfonamidesAntineoplastic Agentsbcl-2-Associated X ProteinBridged Bicyclo Compounds, HeterocyclicMyeloid Cell Leukemia Sequence 1 ProteinNaphthalenesProto-Oncogene Proteins c-bcl-2Spiro CompoundsSulfonamidestapotoclaxvenetoclax

Identifiers

PMID37088806
PMCPMC10123065
OpenAlexW4366821599

What OpenQuestion holds

Textmetadata
LicenceCC BY
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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.