ArticleCold Spring Harbor molecular case studies2015
Complete hematologic response of early T-cell progenitor acute lymphoblastic leukemia to the γ-secretase inhibitor BMS-906024: genetic and epigenetic findings in an outlier case.
Article in Cold Spring Harbor molecular case studies, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 52 citations in OpenAlex.
- Clonal origin tracing and integrated biomarker analysis in aHaematologica · 2026Article
- Decoding notch signaling pathway: an updated insight into its role in colorectal cancer progression and therapy.Cancer cell international · 2026Review
- Notch Inhibitors and BH3 Mimetics in T-Cell Acute Lymphoblastic Leukemia.International journal of molecular sciences · 2024Review
- Mechanism of Notch Signaling Pathway in Malignant Progression of Glioblastoma and Targeted Therapy.Biomolecules · 2024Review
- Developing Targeted Therapies for T Cell Acute Lymphoblastic Leukemia/Lymphoma.Current hematologic malignancy reports · 2023Review
- Targeted therapy and immunotherapy for T cell acute lymphoblastic leukemia/lymphoma.Annals of hematology · 2023Review
- Co-Occurring CSF3R W791* Germline and Somatic T618I Driver Mutations Induce Early CNL and Clonal Progression to Mixed Phenotype Acute Leukemia.Current oncology (Toronto, Ont.) · 2022Article
- Inside the biology of early T-cell precursor acute lymphoblastic leukemia: the perfect trick.Biomarker research · 2021Review
- Next-generation sequencing in thyroid cancers: do targetable alterations lead to a therapeutic advantage?: A multicenter experience.Medicine · 2021Article
- Redox Control in Acute Lymphoblastic Leukemia: From Physiology to Pathology and Therapeutic Opportunities.Cells · 2021Review
- Article
- "Root"ing for successful T-ALL treatment.Blood · 2021Article
- Progress in research on childhood T-cell acute lymphocytic leukemia, Notch1 signaling pathway, and its inhibitors: A review.Bosnian journal of basic medical sciences · 2021Review
- B7-H6 is a new potential biomarker and therapeutic target of T-lymphoblastic lymphoma.Annals of translational medicine · 2021Article
- Notch inhibitors induce diarrhea, hypercrinia and secretory cell metaplasia in the human colon.EXCLI journal · 2021Article
- Advances of target therapy on NOTCH1 signaling pathway in T-cell acute lymphoblastic leukemia.Experimental hematology & oncology · 2020Review
- Review
- Pharmacological disruption of the Notch transcription factor complex.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Blockade of Oncogenic NOTCH1 with the SERCA Inhibitor CAD204520 in T Cell Acute Lymphoblastic Leukemia.Cell chemical biology · 2020Article
- Enhancers and MYC interplay in hematopoiesis.Journal of molecular medicine (Berlin, Germany) · 2020Review
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15 authors at 7 institutions in 1 country.
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Abstract
Notch pathway antagonists such as γ-secretase inhibitors (GSIs) are being tested in diverse cancers, but exceptional responses have yet to be reported. We describe the case of a patient with relapsed/refractory early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL) who achieved a complete hematologic response following treatment with the GSI BMS-906024. Whole-exome sequencing of leukemic blasts revealed heterozygous gain-of-function driver mutations in NOTCH1, CSF3R, and PTPN11, and a homozygous/hemizygous loss-of-function mutation in DNMT3A. The three gain-of-function mutations were absent from remission marrow cells, but the DNMT3A mutation persisted in heterozygous form in remission marrow, consistent with an origin for the patient's ETP-ALL from clonal hematopoiesis. Ex vivo culture of ETP-ALL blasts confirmed high levels of activated NOTCH1 that were repressed by GSI treatment, and RNA-seq documented that GSIs downregulated multiple known Notch target genes. Surprisingly, one potential target gene that was unaffected by GSIs was MYC, a key Notch target in GSI-sensitive T-ALL of cortical T-cell type. H3K27ac super-enhancer landscapes near MYC showed a pattern previously reported in acute myeloid leukemia (AML) that is sensitive to BRD4 inhibitors, and in line with this ETP-ALL blasts downregulated MYC in response to the BRD4 inhibitor JQ1. To our knowledge, this is the first example of complete response of a Notch-mutated ETP-ALL to a Notch antagonist and is also the first description of chromatin landscapes associated with ETP-ALL. Our experience suggests that additional attempts to target Notch in Notch-mutated ETP-ALL are merited.
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