ArticleHaematologica2022
Targeting MCL-1 dysregulates cell metabolism and leukemia-stroma interactions and resensitizes acute myeloid leukemia to BCL-2 inhibition.
Article in Haematologica, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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Who cites it
74 citing papers in PubMed.
- G3BP2 confers venetoclax resistance by stabilizing ELF1-mediated MCL1 transcription in acute myeloid leukemia.Leukemia · 2026Article
- Venetoclax for elderly patients with acute myeloid leukaemia unfit for intensive chemotherapy: Prospects, resistance mechanisms and management strategies.Clinical and translational medicine · 2026Review
- Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.Cell death & disease · 2026Article
- NEK2 drives pathogenesis, drug resistance, and LMP1 expression in EBV-positive non-Hodgkin lymphoma.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Myeloid Cell Leukemia 1 and Hexokinase 2 Directly Interact to Form a Glucose Metabolic Regulatory Axis.Cells · 2026Article
- Metabolomics using anion-exchange chromatography mass spectrometry for the analysis of cells, tissues and biofluids.Nature protocols · 2026Review
- Inhibition of CDK9 enhances AML cell death induced by combined venetoclax and azacitidine.Molecular oncology · 2026Article
- Targeting BCL-XL for degradation synergizes with gemcitabine against cholangiocarcinoma.BMC medicine · 2026Article
- Targeting the Menin-KMT2A interaction in leukemia: Lessons learned and future directions.International journal of cancer · 2026Review
- Article
- Integrative Bioinformatics Reveals Novel Molecular Mechanisms and Therapeutic Targets in Acute Myeloid Leukaemia.Journal of cellular and molecular medicine · 2026Article
- Single-cell transcriptomic characterization of a human MDS hematopoietic dataset and in vitro validation of apoptosis-related venetoclax resistance in human MDS-L cells.Frontiers in cell and developmental biology · 2026Article
- Hippo-YAP/TAZ Signaling in Hematological Malignancies: Molecular Mechanisms, Pathway Crosstalk and Therapeutic Potential.Cancer management and research · 2026Review
- Triplet regimens for all: genomically agnostic approaches to improve on HMA + VEN in AML?Hematology. American Society of Hematology. Education Program · 2025Review
- Stroma-driven horizontal transfer of TCA-related proteins mediates metabolic plasticity and imatinib resistance in chronic myeloid leukemia.Cell communication and signaling : CCS · 2025Article
- MCL1 modulates mTORC1 signaling to promote bioenergetics and tumorigenesis.Nature communications · 2025Article
- Article
- Genes-first and phenotypes-first paths to treatment resistance in hematological malignancies.Cell death & disease · 2025Review
- Apoptosis-targeting BH3 mimetics: transforming treatment for patients with acute myeloid leukaemia.Nature reviews. Clinical oncology · 2025Review
- Targeting the BCL2 Family: Advances and Challenges in BH3 Mimetic-Based Therapies.International journal of molecular sciences · 2025Review
14 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors.
Funding
Abstract
MCL-1 and BCL-2 are both frequently overexpressed in acute myeloid leukemia and critical for the survival of acute myeloid leukemia cells and acute myeloid leukemia stem cells. MCL-1 is a key factor in venetoclax resistance. Using genetic and pharmacological approaches, we discovered that MCL-1 regulates leukemia cell bioenergetics and carbohydrate metabolisms, including the TCA cycle, glycolysis and pentose phosphate pathway and modulates cell adhesion proteins and leukemia-stromal interactions. Inhibition of MCL-1 sensitizes to BCL-2 inhibition in acute myeloid leukemia cells and acute myeloid leukemia stem/progenitor cells, including those with intrinsic and acquired resistance to venetoclax through cooperative release of pro-apoptotic BIM, BAX, and BAK from binding to anti-apoptotic BCL-2 proteins and inhibition of cell metabolism and key stromal microenvironmental mechanisms. The combined inhibition of MCL-1 by MCL-1 inhibitor AZD5991 or CDK9 inhibitor AZD4573 and BCL-2 by venetoclax greatly extended survival of mice bearing patient-derived xenografts established from an acute myeloid leukemia patient who acquired resistance to venetoclax/decitabine. These results demonstrate that co-targeting MCL-1 and BCL-2 improves the efficacy of and overcomes preexisting and acquired resistance to BCL-2 inhibition. Activation of metabolomic pathways and leukemia-stroma interactions are newly discovered functions of MCL-1 in acute myeloid leukemia, which are independent from canonical regulation of apoptosis by MCL-1. Our data provide new mechanisms of synergy and rationale for co-targeting MCL-1 and BCL-2 clinically in patients with acute myeloid leukemia and potentially other cancers.
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