ArticleBlood advances2019
Hematopoietic cytokines mediate resistance to targeted therapy in FLT3-ITD acute myeloid leukemia.
Article in Blood advances, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 56 citations in OpenAlex.
- Review
- Disrupting the CBFβ-SMMHC-RUNX1 oncogenic protein-protein interaction in inv(16) AML: from fusion biology to targeted therapy.Discover oncology · 2026Review
- Neuroinflammatory changes in acute myeloid leukemia: Evidence for blood-brain barrier disruption and glial activation.HemaSphere · 2026Article
- Dual FLT3/PIM inhibitor dapolsertib in acute myeloid leukemia: results from the phase 1/2 DIAMOND-01 trial.Blood neoplasia · 2026Article
- Aberrant CD25 and Increased CD123 Expression Are Common in Acute Myeloid Leukemia withCancers · 2026Article
- FLT3: A 35-Year Voyage from Discovery to the Next Generation of Targeted Therapy in AML.Cancers · 2025Review
- Novel molecular mechanisms of FLT3 deregulation: from the acute myeloid leukemia experience to therapeutic insights in acute lymphoblastic leukemia.Molecular cancer · 2025Review
- Cytokine-mediated CAR T therapy resistance in AML.Nature medicine · 2024Article
- The Dual PIM/FLT3 Inhibitor MEN1703 Combines Synergistically With Gilteritinib in FLT3-ITD-Mutant Acute Myeloid Leukaemia.Journal of cellular and molecular medicine · 2024Article
- In vivo models of subclonal oncogenesis and dependency in hematopoietic malignancy.Cancer cell · 2024Article
- FLT3 targeting in the modern era: from clonal selection to combination therapies.International journal of hematology · 2024Review
- Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1.iScience · 2024Article
- Pim Kinase Inhibitors Increase Gilteritinib Cytotoxicity in FLT3-ITD Acute Myeloid Leukemia Through GSK-3β Activation and c-Myc and Mcl-1 Proteasomal Degradation.Cancer research communications · 2024Article
- FLT3 tyrosine kinase inhibition modulates PRC2 and promotes differentiation in acute myeloid leukemia.Leukemia · 2024Article
- LNS8801 inhibits Acute Myeloid Leukemia by Inducing the Production of Reactive Oxygen Species and Activating the Endoplasmic Reticulum Stress Pathway.Cancer research communications · 2023Article
- Evaluation of hypereosinophilia in a case ofCold Spring Harbor molecular case studies · 2023Article
- How ITD Insertion Sites Orchestrate the Biology and Disease of FLT3-ITD-Mutated Acute Myeloid Leukemia.Cancers · 2023Review
- Rational polypharmacological targeting of FLT3, JAK2, ABL, and ERK1 suppresses the adaptive resistance to FLT3 inhibitors in AML.Blood advances · 2023Article
- The GSK3β/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors.Cell death discovery · 2023Article
- Sitravatinib as a potent FLT3 inhibitor can overcome gilteritinib resistance in acute myeloid leukemia.Biomarker research · 2023Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Activating mutations in Fms-like tyrosine kinase 3 (FLT3) occur in ∼30% of adult cases of acute myeloid leukemia (AML). Selective second- and third-generation FLT3 inhibitors have shown significant clinical activity in patients with relapsed FLT3-mutant AML. However, clearance of FLT3-mutant clones does not consistently occur, and disease will progress in most patients after an initial response. This scenario challenges the model of FLT3-mutant AML being oncogene addicted, and it suggests that redundant signaling pathways regulate AML cell survival after FLT3 inhibition. We show that primary FLT3-mutant AML cells escape apoptosis induced by FLT3 inhibition in vitro in the presence of cytokines produced normally in the bone marrow, particularly granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3). Despite reactivating canonical FLT3-signaling pathways, GM-CSF and IL-3 maintain cell survival without rescuing proliferation. Cytokine-mediated resistance through GM-CSF and IL-3 is dependent on JAK kinase, STAT5, and proviral integration site of Moloney murine leukemia virus (PIM) but not MAPK or mammalian target of rapamycin signaling. Cotreatment with FLT3 inhibitors and inhibitors of JAK or PIM kinases blocks GM-CSF and IL-3 rescue of cell survival in vitro and in vivo. Altogether, these data provide a strong rationale for combination therapy with FLT3 inhibitors to potentially improve clinical responses in AML.
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