ArticleBlood2016
All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo.
Article in Blood, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
35 citing papers in PubMed, 54 citations in OpenAlex.
- Revisiting retinoic acid in AML therapy: mechanisms of action and rational combination strategies.British journal of cancer · 2026Review
- Reawakening Differentiation Therapy in Acute Myeloid Leukemia: A Comprehensive Review of ATRA-Based Combination Strategies.Current oncology (Toronto, Ont.) · 2026Review
- FLT3: A 35-Year Voyage from Discovery to the Next Generation of Targeted Therapy in AML.Cancers · 2025Review
- RNA activation ofMolecular therapy. Nucleic acids · 2025Article
- Screening for Antileukemia Agents in FMS-like Tyrosine Kinase 3 (FLT3)-Mutated Acute Myeloid Leukemia Cells.ACS pharmacology & translational science · 2025Article
- Arsenic trioxide for reprogramming the bone marrow microenvironment to eliminate acute myeloid leukemia blasts.HemaSphere · 2025Article
- Targeting rapid TKI-induced AXL upregulation overcomes adaptive ERK reactivation and exerts antileukemic effects in FLT3/ITD acute myeloid leukemia.Molecular oncology · 2025Article
- Overcoming the sorafenib resistance mechanism in FLT3-mutated acute myeloid leukemia: molecular basis and new targets.Frontiers in oncology · 2025Review
- All-trans retinoic acid potentiates cell death induced by quizartinib in acute myeloid leukemia with FLT3-ITD mutations.Annals of hematology · 2024Article
- Concomitant targeting of FLT3 and SPHK1 exerts synergistic cytotoxicity in FLT3-ITDCell communication and signaling : CCS · 2024Article
- History of Developing Acute Promyelocytic Leukemia Treatment and Role of Promyelocytic Leukemia Bodies.Cancers · 2024Review
- Emerging and Future Targeted Therapies for Pediatric Acute Myeloid Leukemia: Targeting the Leukemia Stem Cells.Biomedicines · 2023Review
- The transcription factor HIF2α partakes in the differentiation block of acute myeloid leukemia.EMBO molecular medicine · 2023Article
- Venetoclax Overcomes Sorafenib Resistance in Acute Myeloid Leukemia by Targeting BCL2.Biology · 2023Article
- The DDUP protein encoded by the DNA damage-induced CTBP1-DT lncRNA confers cisplatin resistance in ovarian cancer.Cell death & disease · 2023Article
- Dual inhibition of EZH2 and G9A/GLP histone methyltransferases by HKMTI-1-005 promotes differentiation of acute myeloid leukemia cells.Frontiers in cell and developmental biology · 2023Article
- All-trans retinoic acid induces differentiation in primary acute myeloid leukemia blasts carrying an inversion of chromosome 16.International journal of hematology · 2022Article
- Selective Inhibition of JAK1 Primes STAT5-Driven Human Leukemia Cells for ATRA-Induced Differentiation.Targeted oncology · 2021Article
- FLT3 tyrosine kinase inhibitors synergize with BCL-2 inhibition to eliminate FLT3/ITD acute leukemia cells through BIM activation.Signal transduction and targeted therapy · 2021Article
- Identification of six hub genes and analysis of their correlation with drug sensitivity in acute myeloid leukemia through bioinformatics.Translational cancer research · 2021Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
FMS-like tyrosine kinase 3 (FLT3)-mutant acute myeloid leukemia (AML) portends a poor prognosis, and ineffective targeting of the leukemic stem cell (LSC) population remains one of several obstacles in treating this disease. All-trans retinoic acid (ATRA) has been used in several clinical trials for the treatment of nonpromyelocytic AML with limited clinical activity observed. FLT3 tyrosine kinase inhibitors (TKIs) used as monotherapy also achieve limited clinical responses and are thus far unable to affect cure rates in AML patients. We explored the efficacy of combining ATRA and FLT3 TKIs to eliminate FLT3/internal tandem duplication (ITD)(+) LSCs. Our studies reveal highly synergistic drug activity, preferentially inducing apoptosis in FLT3/ITD(+) cell lines and patient samples. Colony-forming unit assays further demonstrate decreased clonogenicity of FLT3/ITD(+) cells upon treatment with ATRA and TKI. Most importantly, the drug combination depletes FLT3/ITD(+) LSCs in a genetic mouse model of AML, and prolongs survival of leukemic mice. Furthermore, engraftment of primary FLT3/ITD(+) patient samples is reduced in mice following treatment with FLT3 TKI and ATRA in combination, with evidence of cellular differentiation occurring in vivo. Mechanistically, we provide evidence that the synergism of ATRA and FLT3 TKIs is at least in part due to the observation that FLT3 TKI treatment upregulates the antiapoptotic protein Bcl6, limiting the drug's apoptotic effect. However, cotreatment with ATRA reduces Bcl6 expression to baseline levels through suppression of interleukin-6 receptor signaling. These studies provide evidence of the potential of this drug combination to eliminate FLT3/ITD(+) LSCs and reduce the rate of relapse in AML patients with FLT3 mutations.
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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.