ArticleLeukemia2022
A unique role of p53 haploinsufficiency or loss in the development of acute myeloid leukemia with FLT3-ITD mutation.
Article in Leukemia, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 13 citations in OpenAlex.
- Bemcentinib as monotherapy and in combination with low-dose cytarabine in acute myeloid leukemia patients unfit for intensive chemotherapy: a phase 1b/2a trial.Nature communications · 2025Trial
- Bone marrow sympathetic neuropathy is a hallmark of hematopoietic malignancies and it involves severe ultrastructural damage.Experimental hematology & oncology · 2025Article
- IHCH9033, a novel class I HDAC inhibitor, synergizes with FLT3 inhibitor and rescues quizartinib resistance in FLT3-ITD AML via enhancing DNA damage response.Experimental hematology & oncology · 2025Article
- Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia.The Journal of clinical investigation · 2024Article
- Cre recombinase promotes leukemogenesis in the presence of both homozygous and heterozygous FLT3-ITD.Leukemia · 2024Article
- Impact of p53-associated acute myeloid leukemia hallmarks on metabolism and the immune environment.Frontiers in pharmacology · 2024Review
- Shift of N-MYC Oncogene Expression in AML Patients Carrying the FLT3-ITD Mutation.Pathophysiology : the official journal of the International Society for Pathophysiology · 2023Article
- Dual inhibition of CHK1/FLT3 enhances cytotoxicity and overcomes adaptive and acquired resistance in FLT3-ITD acute myeloid leukemia.Leukemia · 2023Article
- Clonal Hematopoiesis: Role in Hematologic and Non-Hematologic Malignancies.Mediterranean journal of hematology and infectious diseases · 2022Review
- Murine Models of Acute Myeloid Leukemia.Frontiers in oncology · 2022Review
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Authors and funding
19 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
With an incidence of ~50%, the absence or reduced protein level of p53 is much more common than TP53 mutations in acute myeloid leukemia (AML). AML with FLT3-ITD (internal tandem duplication) mutations has an unfavorable prognosis and is highly associated with wt-p53 dysfunction. While TP53 mutation in the presence of FLT3-ITD does not induce AML in mice, it is not clear whether p53 haploinsufficiency or loss cooperates with FLT3-ITD in the induction of AML. Here, we generated FLT3-ITD knock-in; p53 knockout (heterozygous and homozygous) double-transgenic mice and found that both alterations strongly cooperated in the induction of cytogenetically normal AML without increasing the self-renewal potential. At the molecular level, we found the strong upregulation of Htra3 and the downregulation of Lin28a, leading to enhanced proliferation and the inhibition of apoptosis and differentiation. The co-occurrence of Htra3 overexpression and Lin28a knockdown, in the presence of FLT3-ITD, induced AML with similar morphology as leukemic cells from double-transgenic mice. These leukemic cells were highly sensitive to the proteasome inhibitor carfilzomib. Carfilzomib strongly enhanced the activity of targeting AXL (upstream of FLT3) against murine and human leukemic cells. Our results unravel a unique role of p53 haploinsufficiency or loss in the development of FLT3-ITD + AML.
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