ArticleLeukemia2015
Activating c-KIT mutations confer oncogenic cooperativity and rescue RUNX1/ETO-induced DNA damage and apoptosis in human primary CD34+ hematopoietic progenitors.
Article in Leukemia, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 50 citations in OpenAlex.
- Targeting HASPIN kinase disrupts SR protein-mediated RNA splicing and synergizes with BCL-2 inhibitor venetoclax in AML.Blood neoplasia · 2025Article
- Cellular hierarchy for understanding heterogeneity of acute myeloid leukaemia with t(8;21)/RUNX1-RUNX1T1.Clinical & translational immunology · 2025Article
- Pediatric acute myeloid leukemia with t(8;21) and KIT mutation treatment with avapritinib post-stem cell transplantation: a report of four cases.Annals of hematology · 2024Article
- Engineering an inducible leukemia-associated fusion protein enables large-scale ex vivo production of functional human phagocytes.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Combination of eriocalyxin B and homoharringtonine exerts synergistic anti-tumor effects against t(8;21) AML.Acta pharmacologica Sinica · 2024Article
- Review
- CSF3R T618I Collaborates With RUNX1-RUNX1T1 to Expand Hematopoietic Progenitors and Sensitizes to GLI Inhibition.HemaSphere · 2023Article
- Defined Human Leukemic CD34+ Liquid Cultures to Study HDAC/Transcriptional Repressor Complexes.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Transcriptional variability accelerates preleukemia by cell diversification and perturbation of protein synthesis.Science advances · 2022Article
- Mutated KIT Tyrosine Kinase as a Novel Molecular Target in Acute Myeloid Leukemia.International journal of molecular sciences · 2022Review
- Reviewing cancer's biology: an eclectic approach.Journal of the Egyptian National Cancer Institute · 2021Review
- AML1/ETO and its function as a regulator of gene transcription via epigenetic mechanisms.Oncogene · 2021Review
- Review
- Expression of RUNX1-ETO Rapidly Alters the Chromatin Landscape and Growth of Early Human Myeloid Precursor Cells.Cell reports · 2020Article
- An update on the molecular pathogenesis and potential therapeutic targeting of AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1.Blood advances · 2020Review
- Inhibition of the mutated c-KIT kinase in AML1-ETO-positive leukemia cells restores sensitivity to PARP inhibitor.Blood advances · 2019Article
- Epigenetic Modifications in Acute Myeloid Leukemia: Prognosis, Treatment, and Heterogeneity.Frontiers in genetics · 2019Review
- The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation.Cancer cell · 2018Article
- Amyloid precursor protein has clinical and prognostic significance in AML1-ETO-positive acute myeloid leukemia.Oncology letters · 2018Article
- A novel epigeneticEMBO molecular medicine · 2017Article
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The RUNX1/ETO (RE) fusion protein, which originates from the t(8;21) chromosomal rearrangement, is one of the most frequent translocation products found in de novo acute myeloid leukemia (AML). In RE leukemias, activated forms of the c-KIT tyrosine kinase receptor are frequently found, thereby suggesting oncogenic cooperativity between these oncoproteins in the development and maintenance of t(8;21) malignancies. In this report, we show that activated c-KIT cooperates with a C-terminal truncated variant of RE, REtr, to expand human CD34+ hematopoietic progenitors ex vivo. CD34+ cells expressing both oncogenes resemble the AML-M2 myeloblastic cell phenotype, in contrast to REtr-expressing cells which largely undergo granulocytic differentiation. Oncogenic c-KIT amplifies REtr-depended clonogenic growth and protects cells from exhaustion. Activated c-KIT reverts REtr-induced DNA damage and apoptosis. In the presence of activated c-KIT, REtr-downregulated DNA-repair genes are re-expressed leading to an enhancement of DNA-repair efficiency via homologous recombination. Together, our results provide new mechanistic insight into REtr and c-KIT oncogenic cooperativity and suggest that augmented DNA repair accounts for the increased chemoresistance observed in t(8;21)-positive AML patients with activated c-KIT mutations. This cell-protective mechanism might represent a new therapeutic target, as REtr cells with activated c-KIT are highly sensitive to pharmacological inhibitors of DNA repair.
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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.