ArticleBlood2023
Erythroid/megakaryocytic differentiation confers BCL-XL dependency and venetoclax resistance in acute myeloid leukemia.
Article in Blood, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers, 1 of them a synthesis that pooled it.
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Who cites it
77 citing papers in PubMed, 1 synthesis or guideline pooled it, 113 citations in OpenAlex.
- Acute myeloid leukemia with bipotential erythroid and megakaryocytic differentiation: a case series and literature review.Journal of hematopathology · 2025Pooled it
- Azacitidine, Venetoclax, and Magrolimab in Newly Diagnosed and Relapsed Refractory Acute Myeloid Leukemia: Phase Ib/II Study and Correlative Analysis.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
- Sensitivity to ATR-CHK1 pathway inhibition in MDS/AML is enhanced by SRSF2 mutations and reduced by RUNX1 loss.Leukemia · 2026Article
- Revisiting retinoic acid in AML therapy: mechanisms of action and rational combination strategies.British journal of cancer · 2026Review
- Wired to Survive: How AML Cytogenetics Shape Apoptotic Dependence and Venetoclax Resistance.Genes · 2026Review
- m6A and NuRD complexes regulate monocytic differentiation and resistance to BCL2/BCL2L1 inhibitors in acute myeloid leukemia.Haematologica · 2026Article
- Distinct stem cell identities converge into shared erythroid stress in ERCC6L2 disease and Shwachman-Diamond syndrome.HemaSphere · 2026Article
- Epidemiology and prognostic factors of acute erythroid leukemia.Translational cancer research · 2026Article
- Targeting the PBX1-BCL2L1 axis as a therapeutic strategy in colorectal cancer.Cell death discovery · 2026Article
- Review
- Targeting BCL-xL in Myeloid Malignancies: From Inhibitors to PROTAC.Journal of cellular and molecular medicine · 2026Review
- Resistance to Targeted Therapy in AML: Current Challenges and Emerging Treatment Strategies.Journal of clinical medicine · 2026Review
- C-C motif chemokine receptor-like 2 promotes the interferon-γ signaling response in myeloid neoplasms with erythroid differentiation and mutatedHaematologica · 2026Article
- Predictors of response and rational combinations for the novel MCL-1 inhibitor MIK665 in acute myeloid leukemia.Molecular oncology · 2026Article
- Deep cytomorphology identifies erythroid skewing and monocytic morphology to predict TKI sensitivity in CML patients.HemaSphere · 2026Article
- CDK4/6 inhibition overcomes venetoclax resistance mechanisms with enhanced combination activity in acute myeloid leukemia.Cell reports. Medicine · 2026Article
- Article
- BCL-XL drives fibrotic and leukemic progression in myeloproliferative neoplasms.Frontiers in immunology · 2026Article
- Cell death in uveitis: pyroptosis, ferroptosis, apoptosis, and beyond.Frontiers in immunology · 2026Review
- Drivers of clinical resistance to venetoclax and hypomethylating agents in acute myeloid leukemia and strategies for improving efficacy.HemaSphere · 2026Article
17 more citing papers are in PubMed but not listed here.
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Authors and funding
29 authors at 6 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Myeloid neoplasms with erythroid or megakaryocytic differentiation include pure erythroid leukemia, myelodysplastic syndrome with erythroid features, and acute megakaryoblastic leukemia (FAB M7) and are characterized by poor prognosis and limited treatment options. Here, we investigate the drug sensitivity landscape of these rare malignancies. We show that acute myeloid leukemia (AML) cells with erythroid or megakaryocytic differentiation depend on the antiapoptotic protein B-cell lymphoma (BCL)-XL, rather than BCL-2, using combined ex vivo drug sensitivity testing, genetic perturbation, and transcriptomic profiling. High-throughput screening of >500 compounds identified the BCL-XL-selective inhibitor A-1331852 and navitoclax as highly effective against erythroid/megakaryoblastic leukemia cell lines. In contrast, these AML subtypes were resistant to the BCL-2 inhibitor venetoclax, which is used clinically in the treatment of AML. Consistently, genome-scale CRISPR-Cas9 and RNAi screening data demonstrated the striking essentiality of BCL-XL-encoding BCL2L1 but not BCL2 or MCL1, for the survival of erythroid/megakaryoblastic leukemia cell lines. Single-cell and bulk transcriptomics of patient samples with erythroid and megakaryoblastic leukemias identified high BCL2L1 expression compared with other subtypes of AML and other hematological malignancies, where BCL2 and MCL1 were more prominent. BCL-XL inhibition effectively killed blasts in samples from patients with AML with erythroid or megakaryocytic differentiation ex vivo and reduced tumor burden in a mouse erythroleukemia xenograft model. Combining the BCL-XL inhibitor with the JAK inhibitor ruxolitinib showed synergistic and durable responses in cell lines. Our results suggest targeting BCL-XL as a potential therapy option in erythroid/megakaryoblastic leukemias and highlight an AML subgroup with potentially reduced sensitivity to venetoclax-based treatments.
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Registered trials
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.