Affinage

FLT3

Receptor-type tyrosine-protein kinase FLT3 · UniProt P36888

Length
993 aa
Mass
112.9 kDa
Annotated
2026-06-09
100 papers in source corpus 23 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FLT3 (FLK2) is a class III receptor tyrosine kinase expressed on CD34+ hematopoietic progenitors and leukemic blasts that drives proliferative expansion and survival of multipotent and lineage-restricted progenitors (PMID:8384358, PMID:8637232, PMID:31217189). Its ligand FL, produced as a membrane-bound precursor that is proteolytically processed to a soluble form, synergizes with IL-3, IL-6, and GM-CSF to stimulate stem and primitive progenitor populations (PMID:8145851); ligand engagement of the extracellular domain induces receptor dimerization and autophosphorylation, and agonist antibodies against the ectodomain are sufficient to mimic this activation (PMID:8384358, PMID:8637232). The mature, complex-glycosylated receptor recruits and phosphorylates PLC-γ1, PI3K p85, Shc, Grb2, and SRC-family kinases at specific phosphotyrosine sites, with SFKs routing RAS/ERK signaling through GAB2/SHC and providing negative feedback via the E3 ligase CBL, while PI3K coupling is dispensable for mitogenesis and receptor internalization (PMID:7681159, PMID:7692230, PMID:8702727, PMID:30552988). During development FLT3 is genetically required for propagation of a common lymphoid/myeloid progenitor and acts in epistasis with c-KIT in multipotent progenitor maintenance; fate mapping places a non-self-renewing Flk2+ stage on the path to all mature lineages while excluding it from HSC self-renewal (PMID:7621074, PMID:21726834, PMID:31217189). Internal tandem duplication (ITD) mutations in the juxtamembrane domain cause ligand-independent, dimerization-driven constitutive kinase activation that confers factor-independent growth and a myeloproliferative disorder, signaling through PI3K/AKT, RAS/MAPK and aberrantly strong STAT5 while repressing myeloid transcription factors C/EBPβ and PU.1 to block differentiation (PMID:12042700, PMID:16146838, PMID:16263569). Oncogenic FLT3 additionally phosphorylates the CDK inhibitor p27Kip1 at Y88 to neutralize cell-cycle inhibition, drives an HCK/CDK6 proliferative axis, and cooperates with phosphorylated RUNX1 (and its target HHEX) to enforce the differentiation block (PMID:28522571, PMID:31217189, PMID:28213513). FLT3-ITD localization and signaling are tuned post-translationally: ZDHHC6-mediated S-palmitoylation retains the receptor in the ER and restricts output to constitutive STAT5, whereas loss of palmitoylation redirects it to the plasma membrane and rewires signaling to AKT/ERK, and PRMT1-mediated arginine methylation at R972/973 supports AML maintenance independently of kinase activity (PMID:31217189, PMID:34111291). FLT3 expression is set by MYB binding its promoter and C/EBPα binding an intronic module (PMID:23340802).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1993 High

    Established that FLT3 is a functional tyrosine kinase whose ligand-induced catalytic activation is the basis of cellular transformation, defining the receptor's core enzymatic mechanism.

    Evidence Active-site mutagenesis and a CSF-1R/FLT3 chimeric receptor scored by anchorage-independent growth in COS-1 cells

    PMID:8384358

    Open questions at the time
    • Native ligand not yet identified
    • Downstream effectors undefined
  2. 1993 High

    Defined FLT3 as a glycosylated cell-surface receptor maturing from a high-mannose to a complex-carbohydrate form, linking glycan processing to surface display.

    Evidence Pulse-chase, N-glycosidase F digestion and cell-surface labeling of COS-7 transfectants

    PMID:7681159

    Open questions at the time
    • Functional significance of ligand-independent tyrosine phosphorylation unclear
    • No structural model of the receptor
  3. 1993 High

    Identified the proximal signal transducers physically recruited to the activated receptor, mapping the immediate signaling complex.

    Evidence Chimeric CSF-1R/FLK2 receptor with reciprocal co-IP and mitogenesis/IL-3-independence readouts in NIH 3T3 and Ba/F3 cells

    PMID:7692230

    Open questions at the time
    • Relative contribution of each effector to proliferation not resolved
    • Cell-type differences in p85/Shc phosphorylation unexplained
  4. 1994 High

    Purified and cloned the FLT3 ligand, establishing that a membrane-bound precursor is processed to a soluble cytokine that synergizes with other factors on stem/progenitor cells.

    Evidence Protein purification to homogeneity, partial sequencing, cDNA cloning and proliferation assays from mouse thymic stroma

    PMID:8145851

    Open questions at the time
    • Protease responsible for shedding not identified
    • Stoichiometry of ligand-receptor dimerization not defined
  5. 1995 High

    Assigned FLT3 a physiological role in hematopoiesis and placed it genetically alongside c-KIT, distinguishing in vivo function from cell-line biochemistry.

    Evidence Flk2/flt3 knockout and flk2/c-kit double-knockout mice with bone marrow transplantation and lineage flow cytometry

    PMID:7621074

    Open questions at the time
    • Molecular basis of B-lineage selectivity unclear
    • Mechanism of KIT epistasis not defined at the signaling level
  6. 1996 Medium

    Showed the extracellular domain alone is sufficient for activation and mapped FLT3 surface expression to CD34+ progenitors and leukemic blasts, tying the receptor to leukemia-relevant cells.

    Evidence Agonist monoclonal antibodies and 3-color flow cytometry

    PMID:8637232

    Open questions at the time
    • Single-lab antibody mimicry
    • Quantitative comparison to native ligand activation lacking
  7. 1996 Medium

    Demonstrated that FLT3 overexpressed on primary AML blasts is functional and ligand-responsive, validating the receptor as active in patient disease.

    Evidence FL stimulation and anti-FLT3 immunoblot autophosphorylation assays on primary leukemic marrow

    PMID:8562934

    Open questions at the time
    • Does not establish causal role in leukemogenesis
    • Downstream consequences in blasts not measured
  8. 1996 High

    Used loss-of-coupling mutagenesis to show PI3K is dispensable for FLT3 mitogenesis and internalization, refining which effectors are essential versus auxiliary.

    Evidence PI3K-binding-site mutants in NIH 3T3 and Ba/F3 cells with proliferation and down-regulation assays

    PMID:8702727

    Open questions at the time
    • PI3K function in other cell contexts not excluded
    • Compensating effectors not identified
  9. 2002 High

    Defined the oncogenic ITD mechanism: juxtamembrane duplications cause ligand-independent constitutive kinase activation that transforms cells and causes myeloproliferative disease in vivo, linking a specific mutation to leukemia.

    Evidence Retroviral ITD transduction of Ba/F3, 32D and primary murine marrow with factor-independence, signaling analysis, transplantation and kinase-dead controls

    PMID:12042700

    Open questions at the time
    • Quantitative difference in signaling vs wild-type not yet detailed
    • Mechanism of ligand-independent dimerization not structurally defined
  10. 2005 Medium

    Distinguished oncogenic from physiological signaling by showing mutant FLT3 aberrantly activates STAT5 and represses myeloid transcription factors, and that ITD-driven dimerization blocks differentiation reversibly by TKI.

    Evidence Comparative signaling, reporter and gene-expression analysis in wild-type vs mutant FLT3 cell lines; differentiation/apoptosis assays under TKI

    PMID:16146838 PMID:16263569

    Open questions at the time
    • Direct STAT5 target genes in primary cells incompletely mapped
    • Mechanism of C/EBPβ/PU.1 repression not resolved
  11. 2011 High

    Resolved FLT3's exact position in the hematopoietic hierarchy, showing all mature lineages transit a Flk2+ non-self-renewing stage that is excluded from HSC self-renewal.

    Evidence Flk2-Cre x Rosa26 in vivo lineage tracing across steady-state, stress and transplant conditions

    PMID:21726834

    Open questions at the time
    • Does not address whether FLT3 signaling instructs lineage transitions
    • Megakaryocyte/erythroid routing details limited
  12. 2013 Medium

    Established FLT3 as required for proliferative expansion of a common multipotent progenitor and identified an FLT3/HCK/CDK6 axis required for ITD transformation, connecting the receptor to cell-cycle machinery.

    Evidence Flk2 knockout with purified-progenitor transplantation; Cdk6-/- rescue and HCK inhibition in FLT3-ITD AML cells

    PMID:24333663 PMID:27323399

    Open questions at the time
    • How HCK selectively upregulates CDK6 not mechanistically detailed
    • Two separate studies not jointly validated
  13. 2013 Medium

    Defined the transcriptional control of FLT3 itself, identifying MYB and C/EBPα as direct regulators binding promoter and intronic elements.

    Evidence Chromatin accessibility, ChIP and histone-mark analysis in murine AML and primary human AML

    PMID:23340802

    Open questions at the time
    • Single lab
    • Functional impact of each element on FLT3 dosage not quantified
  14. 2017 High

    Identified p27Kip1-Y88 as a direct FLT3 substrate, providing a kinase-to-cell-cycle link by which the receptor inactivates a CDK inhibitor.

    Evidence Co-IP, in vitro kinase assay and AC220 treatment in cell lines and primary AML samples

    PMID:28522571

    Open questions at the time
    • Contribution relative to STAT5/CDK6 routes not quantified
    • Structural basis of p27 recognition unknown
  15. 2017 High

    Showed FLT3-ITD cooperates with phosphorylated RUNX1 (and its target HHEX) to enforce differentiation block and ribosome biogenesis, defining a transcriptional cooperator of the oncogene.

    Evidence Co-expression, RUNX1 inactivation, ChIP and gene-expression analysis in a murine AML model

    PMID:28213513

    Open questions at the time
    • Direct biochemical RUNX1 phosphorylation by FLT3 not isolated
    • Generality across AML subtypes untested
  16. 2018 Medium

    Detailed the SRC-family kinase node downstream of FLT3, showing SFKs route RAS/ERK via GAB2/SHC while negatively feeding back through CBL, with member-specific roles.

    Evidence Co-IP, phosphorylation and SFK knockdown/inhibition studies synthesized in a review

    PMID:30552988

    Open questions at the time
    • Individual SFK assignments rest on aggregated data
    • In vivo relevance of CBL feedback in AML not quantified
  17. 2019 High

    Established arginine methylation as a kinase-independent regulatory layer, identifying PRMT1 as the writer at R972/973 required for FLT3-ITD AML maintenance.

    Evidence Co-IP, mass spectrometry, site-directed mutagenesis, PRMT1 knockout and PDX models

    PMID:31217189

    Open questions at the time
    • Reader of the methyl mark not identified
    • Mechanism of cross-talk with Y969 phosphorylation incompletely defined
  18. 2020 High

    Revealed a population-level feedback loop in which a loss-of-function FLT3 splice variant doubles plasma FL, showing receptor function reciprocally sets ligand levels in humans.

    Evidence RNA-seq identification of a cryptic splice site, GWAS and plasma FL ELISA

    PMID:32581359

    Open questions at the time
    • Cellular source of compensatory ligand not localized
    • Physiological consequence of the truncated protein unmeasured
  19. 2021 High

    Defined S-palmitoylation by ZDHHC6 as a localization switch confining FLT3-ITD to the ER and restricting output to STAT5, with loss redirecting it to the plasma membrane and rewiring to AKT/ERK.

    Evidence Palmitoylation assay, ZDHHC6 knockdown/overexpression, fractionation, signaling analysis and xenotransplant models with primary AML samples

    PMID:34111291

    Open questions at the time
    • Depalmitoylase counter-enzyme not identified
    • Therapeutic exploitability not established
  20. 2021 High

    Mapped a BCL-2-family rewiring after FLT3 inhibition in which BCL-2 sequesters BIM, providing a mechanistic rationale for combining FLT3 TKI with venetoclax.

    Evidence Reciprocal co-IP of BIM with BCL-2/MCL-1/BAX and apoptosis assays in FLT3-ITD cell lines and primary AML

    PMID:34024909

    Open questions at the time
    • Transcriptional vs post-translational basis of BIM shift not separated
    • Clinical durability not addressed by mechanism
  21. 2016 Medium

    Identified DOCK2 as a FLT3-associated Rho-GEF required for proliferation of FLT3-overactive leukemia and modulating TKI/cytarabine sensitivity, expanding the FLT3 interactome.

    Evidence MS interaction screen, co-IP, shRNA knockdown with proliferation/colony assays and xenograft survival

    PMID:27748370

    Open questions at the time
    • Directness of FLT3-DOCK2 binding vs complex association not resolved
    • Rho-GTPase effector downstream of DOCK2 not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct post-translational layers (palmitoylation, arginine methylation, phosphorylation) and transcriptional cooperators are integrated to select STAT5 versus AKT/ERK outputs and enforce differentiation block remains unresolved.
  • No unified model linking localization, PTMs and effector choice
  • Readers/erasers of methyl and acyl marks not fully identified
  • Structural basis of ITD-driven ligand-independent dimerization undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0001618 virus receptor activity 2 GO:0016740 transferase activity 2 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3
Partners
CBLDOCK2FLT3LGGRB2PIK3R1PLCG1PRMT1SHC1

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 FLT3/FLK2 receptor tyrosine kinase has intrinsic tyrosine kinase activity; a point mutation in the conserved phosphoryltransferase domain inactivates catalytic function; a chimeric CSF-1R extracellular domain/FLT3 kinase domain construct demonstrated transforming activity (anchorage-independent growth) upon CSF-1 stimulation, establishing ligand-induced kinase activation as the mechanism of transformation. Site-directed mutagenesis of kinase domain, chimeric receptor construct expressed in COS-1 cells, anchorage-independent growth assay Oncogene High 8384358
1993 FLT3 protein undergoes N-linked glycosylation maturation: a 143 kDa high-mannose form is processed to a 158 kDa complex-carbohydrate form that is expressed on the cell surface. FLT3 is heavily phosphorylated on tyrosine even in the absence of ligand, resembling c-ErbB2. Immunoprecipitation with polyclonal antibodies, pulse-chase analysis in COS-7 transfectants, N-glycosidase F digestion, cell-surface labeling Oncogene High 7681159
1993 Activated FLT3/FLK2 kinase recruits and/or phosphorylates phospholipase C-γ1, Ras-GAP, PI3K p85 subunit, Shc, Grb2, Vav, Fyn, and Src. Physical association with the FLT3 cytoplasmic domain was demonstrated for PLC-γ1, PI3K p85, Shc, Grb2, and Src family kinases, but not for Ras-GAP, Vav, or Nck. Cell-type-specific differences in tyrosine phosphorylation of p85 and Shc were observed. Chimeric CSF-1R/FLK2 receptor in NIH 3T3 and Ba/F3 cells, co-immunoprecipitation, tyrosine phosphorylation assays, factor-independence assay Molecular and cellular biology High 7692230
1994 FLT3 ligand (FL) was purified to homogeneity from mouse thymic stromal cells, partially sequenced, and shown to be encoded by multiple cDNA variants; some contain transmembrane segments indicating a membrane-bound precursor requiring proteolytic processing to release soluble ligand. FL synergizes with IL-3, IL-6, and GM-CSF to stimulate mouse stem cells and a primitive human progenitor population. Protein purification, partial sequencing, cDNA cloning, functional proliferation assays with purified ligand Nature High 8145851
1995 Mice with targeted disruption of flk2/flt3 are viable and healthy but have specific deficiencies in primitive B lymphoid progenitors. Bone marrow transplantation revealed further deficiency in T cell and myeloid reconstitution by mutant stem cells. Double knockout of c-kit and flk2 produced severe reductions in hematopoietic cell numbers and postnatal lethality, establishing genetic epistasis between FLT3 and c-KIT in multipotent progenitor maintenance. Gene targeting (knockout mice), bone marrow transplantation, flow cytometric analysis of hematopoietic populations Immunity High 7621074
1996 Monoclonal antibodies against the FLT3 extracellular domain can mimic FL activity, activating and modulating the receptor, establishing that the extracellular domain is sufficient for receptor activation. FLT3 surface expression is restricted to CD34+ hematopoietic progenitors and leukemic blasts; most CD34+FLT3+ cells co-express CD117 (KIT). Monoclonal antibody generation, functional receptor activation assays, flow cytometry (3-color analysis) Leukemia Medium 8637232
1996 Stimulation of leukemic patient samples with FLT3 ligand results in autophosphorylation of the FLT3 receptor, confirming that overexpressed FLT3 in AML cells is functional and capable of ligand-induced kinase activation. Western blotting with anti-FLT3 antisera, FLT3 ligand stimulation and autophosphorylation assay in primary leukemic bone marrow samples Blood Medium 8562934
1996 PI3K binds to a unique site in the carboxy tail of murine FLT3/FLK2; however, mutant receptors unable to couple to PI3K retain full mitogenic signaling and normal receptor down-regulation in NIH 3T3 fibroblasts and Ba/F3 cells, demonstrating that PI3K is not required for FLT3-mediated mitogenesis or receptor internalization. Mutagenesis of PI3K binding site, transfection into NIH 3T3 and Ba/F3 cells, proliferation assays, receptor down-regulation assays The Journal of biological chemistry High 8702727
2002 FLT3 internal tandem duplication (ITD) mutations in the juxtamembrane domain result in constitutive, ligand-independent tyrosine kinase activation. FLT3-ITD confers factor-independent growth to Ba/F3 and 32D cells, activates STAT, RAS/MAPK, and PI3K/AKT pathways, and causes a myeloproliferative disorder upon retroviral transduction into primary murine bone marrow. Mutations that abrogate kinase activity abolish transforming properties. Retroviral transduction into Ba/F3 and 32D cells, factor-independence assay, signaling pathway analysis, murine bone marrow transduction/transplantation model, kinase-dead mutagenesis Current opinion in hematology High 12042700
2005 Oncogenic FLT3 mutations (ITD and TKD point mutations) result in constitutive activation of downstream pathways shared with wild-type FLT3 (PI3K, Src kinases, MAPK) but additionally cause aberrant strong activation of STAT5 and induction of STAT5 target genes, as well as repression of myeloid transcription factors C/EBPβ and PU.1, which are not activated by wild-type receptor. Signal transduction analysis in cell lines expressing wild-type vs. mutant FLT3, immunoprecipitation, reporter assays, gene expression analysis International journal of hematology Medium 16146838
2011 Lineage tracing using a Flk2-Cre mouse model demonstrated that all mature hematopoietic lineages—including megakaryocyte/erythroid cells—pass through a Flk2-expressing non-self-renewing progenitor stage during steady-state hematopoiesis, after irradiation stress, and upon HSC transplantation. HSC origin and maintenance do not include a Flk2+ stage, dissociating HSC self-renewal from Flk2 expression. In vivo lineage tracing (Flk2-Cre × Rosa26-reporter mice), flow cytometry of all hematopoietic lineages, bone marrow transplantation Cell stem cell High 21726834
2013 Flk2/FLT3 is critical for proliferative expansion of multipotent progenitors common to all lymphoid and myeloid lineages; Flk2 deficiency impairs generation of both lymphoid and myeloid progenitors by abrogating propagation of their common upstream precursor without affecting lineage choice. FLT3-ITD failed to transform primary hematopoietic progenitors from Cdk6-/- mice, and FLT3-ITD signaling upregulates CDK6 through the SRC-family kinase HCK, establishing an FLT3/HCK/CDK6 pathway. Flk2 knockout mice, transplantation of purified progenitors, lineage analysis; separate pathway study using Cdk6-/- mice and HCK inhibition in FLT3-ITD AML cells Experimental hematology; Oncotarget Medium 24333663 27323399
2017 FLT3 and FLT3-ITD directly bind and phosphorylate the CDK inhibitor p27Kip1 at tyrosine residue 88, inactivating its cell-cycle inhibitory function. Inhibition of FLT3-ITD kinase reduced p27-Y88 phosphorylation and caused cell cycle arrest. Phospho-Y88-p27 was detected in primary AML patient samples. Co-immunoprecipitation of FLT3 and p27, in vitro phosphorylation assay, FLT3 inhibitor (AC220) treatment in cell lines and primary AML patient samples, flow cytometry for cell cycle Haematologica High 28522571
2019 PRMT1 methylates FLT3-ITD protein at arginine residues 972/973, promoting AML maintenance. This methylation occurs independently of FLT3 kinase activity and persists following FLT3 kinase inhibition. FLT3-ITD methylation cross-talks with phosphorylation at tyrosine 969. Genetic or pharmacological PRMT1 inhibition blocked FLT3-ITD+ AML cell maintenance. Co-immunoprecipitation, genome-wide analysis, PRMT1 knockout mouse studies, mass spectrometry, site-directed mutagenesis, patient-derived xenograft models Blood High 31217189
2021 FLT3-ITD is S-palmitoylated by the palmitoyl acyltransferase ZDHHC6, which retains FLT3-ITD in the endoplasmic reticulum and restricts signaling to constitutive STAT5 phosphorylation. Disruption of palmitoylation redirects FLT3-ITD to the plasma membrane, rewiring downstream signaling to additionally activate AKT and ERK pathways, and exacerbates leukemia progression in xenotransplant models. Palmitoylation assay, ZDHHC6 knockdown/overexpression, subcellular fractionation, signaling analysis, xenotransplant mouse models, primary AML patient samples Blood High 34111291
2021 FLT3 TKI (gilteritinib/sorafenib) treatment dissociates BIM from MCL-1 but increases BIM-BCL-2 binding. Combined FLT3 TKI + venetoclax (BCL-2 inhibitor) treatment dissociates BIM from both BCL-2 and MCL-1 and increases BIM-BAX binding, driving apoptosis. This mechanistic cross-talk establishes a pro-survival role of BCL-2 as a BIM reservoir following FLT3 inhibition. Co-immunoprecipitation of BIM with BCL-2/MCL-1/BAX, proliferation assays, apoptosis assays in FLT3-ITD cell lines and primary AML samples Signal transduction and targeted therapy High 34024909
2016 DOCK2, a guanine nucleotide exchange factor for Rho GTPases, co-immunoprecipitates with both wild-type FLT3 and FLT3-ITD in leukemia cells. DOCK2 knockdown selectively reduces proliferation and colony formation in FLT3-overactive leukemia cells and sensitizes them to cytarabine and FLT3 inhibitors; prolonged survival in a mouse xenograft model was observed. Mass spectrometry-based protein interaction screen, co-immunoprecipitation, shRNA knockdown, proliferation/colony assays, mouse xenograft model Leukemia Medium 27748370
2013 The transcription factors MYB and C/EBPα directly regulate FLT3 expression: MYB binds the FLT3 promoter and C/EBPα binds an intronic regulatory module, as demonstrated by chromatin accessibility assays and epigenetic markings in murine AML cells and primary human AML patient samples. Chromatin accessibility assays, chromatin immunoprecipitation (ChIP), epigenetic histone mark analysis, gene expression profiling in AML patient samples Leukemia Medium 23340802
2017 FLT3-ITD directly impacts RUNX1 activity by upregulating and phosphorylating RUNX1, which then cooperates with FLT3-ITD to induce AML. Inactivating RUNX1 in FLT3-ITD tumors releases differentiation block and downregulates ribosome biogenesis genes. HHEX was identified as a direct RUNX1 and FLT3-ITD target gene that can substitute for RUNX1 in cooperating with FLT3-ITD. Genetic co-expression experiments in primary hematopoietic progenitors, RUNX1 inactivation, gene expression analysis, ChIP, murine AML model The Journal of experimental medicine High 28213513
2018 Ligand-induced FLT3 dimerization and autophosphorylation creates binding sites for SRC family kinases (SFKs), which are recruited to specific phosphotyrosine residues on FLT3. SFKs regulate downstream RAS/ERK signaling through GAB2 and SHC adaptor proteins, and negatively regulate FLT3 signaling through phosphorylation of the ubiquitin E3 ligase CBL. Individual SFK members have distinct positive vs. negative signaling roles downstream of FLT3. Co-immunoprecipitation, phosphorylation assays, SFK knockdown/inhibition studies, signaling pathway analysis The international journal of biochemistry & cell biology Medium 30552988
2020 A low-frequency intronic FLT3 variant (rs76428106-C) generates a cryptic splice site introducing a stop codon in 30% of transcripts, predicted to encode a truncated protein lacking tyrosine kinase domains (loss-of-function). Each copy of this variant doubles plasma FLT3 ligand levels, demonstrating a compensatory feedback mechanism where reduced FLT3 receptor function elevates ligand. RNA sequencing to identify cryptic splice site, GWAS, plasma FLT3 ligand quantification by ELISA Nature High 32581359
2005 FLT3-ITD mutations activate tyrosine kinase through receptor dimerization in a FLT3 ligand-independent manner, contributing to a block in myeloid differentiation in addition to proliferative and anti-apoptotic signaling. FLT3 tyrosine kinase inhibitors suppress growth and induce apoptosis and differentiation of FLT3-ITD-expressing leukemia cells. Cell line studies with FLT3-ITD expression, differentiation assays, apoptosis assays, TKI treatment experiments Leukemia & lymphoma Medium 16263569

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The roles of FLT3 in hematopoiesis and leukemia. Blood 1221 12176867
2003 The role of FLT3 in haematopoietic malignancies. Nature reviews. Cancer 690 12951584
1995 Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 469 7621074
1994 Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs. Nature 401 8145851
2003 FLT3: ITDoes matter in leukemia. Leukemia 395 12970773
1993 Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells. Blood 311 8394751
1996 Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood 257 8562934
1996 Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells. Leukemia 229 8618433
2017 Midostaurin approved for FLT3-mutated AML. Blood 225 28546144
1996 Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia 203 8637232
2011 All hematopoietic cells develop from hematopoietic stem cells through Flk2/Flt3-positive progenitor cells. Cell stem cell 193 21726834
2009 Structural and functional alterations of FLT3 in acute myeloid leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research 183 19549778
2006 FLT3 mutations: biology and treatment. Hematology. American Society of Hematology. Education Program 170 17124058
2006 New evidence supporting megakaryocyte-erythrocyte potential of flk2/flt3+ multipotent hematopoietic progenitors. Cell 167 16873070
1993 Mitogenic signalling and substrate specificity of the Flk2/Flt3 receptor tyrosine kinase in fibroblasts and interleukin 3-dependent hematopoietic cells. Molecular and cellular biology 166 7692230
2002 Role of FLT3 in leukemia. Current opinion in hematology 159 12042700
2018 FLT3 inhibitors in acute myeloid leukemia. Journal of hematology & oncology 134 30514344
2021 FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm. Blood cancer journal 127 34045454
2008 Flk2+ common lymphoid progenitors possess equivalent differentiation potential for the B and T lineages. Blood 122 18424665
2020 Gilteritinib: potent targeting of FLT3 mutations in AML. Blood advances 116 32208491
1997 Functional and phenotypic characterization of cord blood and bone marrow subsets expressing FLT3 (CD135) receptor tyrosine kinase. Blood 113 9207445
2020 FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease. Nature 110 32581359
1995 Expression of the flt3 receptor and its ligand on hematopoietic cells. Leukemia 109 7630197
1995 Expression of FLT3 receptor and FLT3-ligand in human leukemia-lymphoma cell lines. Leukemia 107 7643626
1993 Characterization of the protein encoded by the flt3 (flk2) receptor-like tyrosine kinase gene. Oncogene 102 7681159
1995 Biology of flt3 ligand and receptor. International journal of hematology 100 8590775
1993 Biochemical characterization and analysis of the transforming potential of the FLT3/FLK2 receptor tyrosine kinase. Oncogene 96 8384358
2012 FLT3 inhibition: a moving and evolving target in acute myeloid leukaemia. Leukemia 95 22797419
2009 FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 94 19467916
2021 FLT3 tyrosine kinase inhibitors synergize with BCL-2 inhibition to eliminate FLT3/ITD acute leukemia cells through BIM activation. Signal transduction and targeted therapy 91 34024909
2017 The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis. International journal of molecular sciences 91 28538663
2017 FLT3-ITD and its current role in acute myeloid leukaemia. Medical oncology (Northwood, London, England) 85 28470536
1998 FLT3: receptor and ligand. Biology and potential clinical application. Cytokine & growth factor reviews 79 9720755
2019 PRMT1-mediated FLT3 arginine methylation promotes maintenance of FLT3-ITD+ acute myeloid leukemia. Blood 78 31217189
1996 The FLK2/FLT3 ligand synergizes with interleukin-7 in promoting stromal-cell-independent expansion and differentiation of human fetal pro-B cells in vitro. Blood 77 8634436
2005 Signal transduction of oncogenic Flt3. International journal of hematology 76 16146838
1996 flk2/flt3 ligand is a potent cofactor for the growth of primitive B cell progenitors. Journal of immunology (Baltimore, Md. : 1950) 73 8543798
2008 Targeting FLT3 for the treatment of leukemia. Seminars in hematology 70 18760705
2005 FLT3 tyrosine kinase inhibitors. International journal of hematology 68 16146839
2016 How I treat FLT3-mutated AML. Blood 65 27872057
2019 Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia. Biomarker research 64 31528345
2014 Targeting FLT3 to treat leukemia. Expert opinion on therapeutic targets 64 25231999
2021 Potential targeting of FLT3 acute myeloid leukemia. Haematologica 63 32703795
2005 Clinical significance of FLT3 in leukemia. International journal of hematology 59 16146837
2004 Flt3 receptor tyrosine kinase as a drug target in leukemia. Current pharmaceutical design 57 15180525
2004 FLT3: receptor and ligand. Growth factors (Chur, Switzerland) 57 15253381
2007 FLT3 inhibition in acute myeloid leukaemia. British journal of haematology 56 17655729
2004 FLT3 mutations in myeloid sarcoma. British journal of haematology 54 15352981
2016 Inhibition of FLT3 in AML: a focus on sorafenib. Bone marrow transplantation 51 27775694
2014 The Biology and Targeting of FLT3 in Pediatric Leukemia. Frontiers in oncology 51 25295230
2009 Mechanisms of resistance to FLT3 inhibitors. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 51 19162530
2004 Normal and oncogenic FLT3. Cellular and molecular life sciences : CMLS 51 15583855
2013 FLT3 inhibitor-induced neutrophilic dermatosis. Blood 50 23687091
2013 Flk2/Flt3 promotes both myeloid and lymphoid development by expanding non-self-renewing multipotent hematopoietic progenitor cells. Experimental hematology 50 24333663
2023 Treatment of older adults with FLT3-mutated AML: Emerging paradigms and the role of frontline FLT3 inhibitors. Blood cancer journal 49 37696819
2021 Depalmitoylation rewires FLT3-ITD signaling and exacerbates leukemia progression. Blood 49 34111291
2002 FLT3 in human hematologic malignancies. Leukemia & lymphoma 49 12400596
2023 A Review of FLT3 Kinase Inhibitors in AML. Journal of clinical medicine 48 37892567
2015 FLT3 INHIBITORS: RECENT ADVANCES AND PROBLEMS FOR CLINICAL APPLICATION. Nagoya journal of medical science 47 25797966
2021 Dendritic cell Flt3 - regulation, roles and repercussions for immunotherapy. Immunology and cell biology 46 34097779
2009 FLT3 inhibition as a targeted therapy for acute myeloid leukemia. Current opinion in oncology 45 19684517
2000 Flt3 ligand (FL) and its influence on immune reactivity. Cytokine 45 10671293
2011 FLT3 inhibitors: a story of the old and the new. Current opinion in hematology 44 21245757
2017 High expression of FLT3 is a risk factor in leukemia. Molecular medicine reports 42 29257272
2023 Flt3- and Tie2-Cre tracing identifies regeneration in sepsis from multipotent progenitors but not hematopoietic stem cells. Cell stem cell 41 36652946
2016 FLT3 Inhibitors for Treating Acute Myeloid Leukemia. Clinical lymphoma, myeloma & leukemia 41 27450971
2022 Role of Biomarkers in FLT3 AML. Cancers 37 35267471
2017 RUNX1 cooperates with FLT3-ITD to induce leukemia. The Journal of experimental medicine 37 28213513
2017 The Future of Targeting FLT3 Activation in AML. Current hematologic malignancy reports 37 28421420
2012 Mapping differentiation pathways from hematopoietic stem cells using Flk2/Flt3 lineage tracing. Cell cycle (Georgetown, Tex.) 37 22895180
1998 Biologic effects and potential clinical applications of Flt3 ligand. Current opinion in hematology 36 9664159
1994 The expression of FMS, KIT and FLT3 in hematopoietic malignancies. Leukemia & lymphoma 36 7519507
2019 The growing landscape of FLT3 inhibition in AML. Hematology. American Society of Hematology. Education Program 35 31808872
2017 FLT3 inhibitors: clinical potential in acute myeloid leukemia. OncoTargets and therapy 35 28223820
2013 C/EBPα and MYB regulate FLT3 expression in AML. Leukemia 34 23340802
2013 FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis in rheumatoid arthritis. Arthritis research & therapy 33 24314260
2024 Understanding mechanisms of resistance to FLT3 inhibitors in adult FLT3-mutated acute myeloid leukemia to guide treatment strategy. Critical reviews in oncology/hematology 32 38917943
2014 FLT3 inhibitors in AML: are we there yet? Current hematologic malignancy reports 32 24682858
2001 FLT3 tyrosine kinase as a target molecule for selective antileukemia therapy. Cancer chemotherapy and pharmacology 32 11587362
1996 Soluble thrombopoietin receptor (Mpl) and granulocyte colony-stimulating factor receptor directly stimulate proliferation of primitive hematopoietic progenitors of mice in synergy with steel factor or the ligand for Flt3/Flk2. Blood 32 8943846
2018 Targeting FLT3 Mutations in Acute Myeloid Leukemia. Cells 31 29316714
1996 Phosphatidylinositol-3' kinase is not required for mitogenesis or internalization of the Flt3/Flk2 receptor tyrosine kinase. The Journal of biological chemistry 31 8702727
2021 Myeloid/lymphoid neoplasms with FLT3 rearrangement. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 30 33990705
2018 Clinical use of FLT3 inhibitors in acute myeloid leukemia. OncoTargets and therapy 30 30410361
2005 Mutant FLT3 signaling contributes to a block in myeloid differentiation. Leukemia & lymphoma 29 16263569
2017 Targeting FLT3 Signaling in Childhood Acute Myeloid Leukemia. Frontiers in pediatrics 28 29209600
2022 "FLipping" the Story: FLT3-Mutated Acute Myeloid Leukemia and the Evolving Role of FLT3 Inhibitors. Cancers 27 35884458
2020 CCL5 mediates target-kinase independent resistance to FLT3 inhibitors in FLT3-ITD-positive AML. Molecular oncology 27 31955503
2016 An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia. Oncotarget 26 27323399
2003 Novel FLT3 tyrosine kinase inhibitors. Expert opinion on investigational drugs 26 14640939
2023 Concomitant targeting of FLT3 and BTK overcomes FLT3 inhibitor resistance in acute myeloid leukemia through the inhibition of autophagy. Haematologica 25 36226489
2023 Mutation spectrum of FLT3 and significance of non-canonical FLT3 mutations in haematological malignancy. British journal of haematology 23 37246158
2018 The role of SRC family kinases in FLT3 signaling. The international journal of biochemistry & cell biology 23 30552988
2016 DOCK2 interacts with FLT3 and modulates the survival of FLT3-expressing leukemia cells. Leukemia 23 27748370
2014 Will FLT3 inhibitors fulfill their promise in acute meyloid leukemia? Current opinion in hematology 23 24468836
1996 Regulatory roles of the ligand for Flk2/Flt3 tyrosine kinase receptor on human hematopoiesis. Stem cells (Dayton, Ohio) 23 8843540
2022 FLT3-targeted treatment for acute myeloid leukemia. International journal of hematology 22 35532877
2024 Quizartinib: a potent and selective FLT3 inhibitor for the treatment of patients with FLT3-ITD-positive AML. Journal of hematology & oncology 21 39538314
2017 FLT3 and FLT3-ITD phosphorylate and inactivate the cyclin-dependent kinase inhibitor p27Kip1 in acute myeloid leukemia. Haematologica 21 28522571
2021 Strategies targeting FLT3 beyond the kinase inhibitors. Pharmacology & therapeutics 20 33811956

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