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BIOMARKER:

FLT3-ITD expression

i
Other names: FLT3, Fms Related Tyrosine Kinase 3, Receptor-Type Tyrosine-Protein Kinase FLT3, Stem Cell Tyrosine Kinase 1, Fms-Like Tyrosine Kinase 3, CD135, FLK-2, STK1, Growth Factor Receptor Tyrosine Kinase Type III, Fetal Liver Kinase 2
Entrez ID:
2ms
Feasible diet and circadian interventions reduce in vivo progression of FLT3-ITD-positive acute myeloid leukemia. (PubMed, Cancer Med)
Mouse models for FLT3-ITD AML show that diet composition and timing slows progression of FLT3-ITD AML growth in vivo, potentially mediated by BMAL1. These interventions to enhance therapy efficacy show preliminary feasibility, as pediatric leukemia patients responded favorable to preparation of macronutrient matched meals.
Preclinical • Journal
|
FLT3 (Fms-related tyrosine kinase 3) • ARNTL (Aryl Hydrocarbon Receptor Nuclear Translocator Like)
|
FLT3 expression • FLT3-ITD expression
2ms
BRCC36 associates with FLT3-ITD to regulate its protein stability and intracellular signaling in acute myeloid leukemia. (PubMed, Cancer Sci)
Thiolutin efficiently affected leukemia cell lines expressing FLT3-ITD cell viability and exhibited mutual synergies with quizartinib, a standard clinical medicine for AML. Furthermore, mutation of the lysine at 609 of ITD led to significant suppression of K63 polyubiquitination and decreased its stability, suggesting that K609 is a critical site for K63 ubiquitination specifically recognized by BRCC36. These data indicate that BRCC36 is a specific regulator for FLT3-ITD, which may shed light on developing a novel therapeutic approach for AML.
Journal • BRCA Biomarker
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FLT3 (Fms-related tyrosine kinase 3) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset)
|
FLT3-ITD mutation • FLT3 mutation • FLT3 wild-type • FLT3 expression • FLT3-ITD expression
|
Vanflyta (quizartinib)
2ms
Pim kinase inhibitors increase gilteritinib cytotoxicity in FLT3-ITD acute myeloid leukemia through GSK-3β activation and c-Myc and Mcl-1 proteasomal degradation. (PubMed, Cancer Res Commun)
Cytotoxicity, apoptosis and protein expression and turnover were measured in FLT3-ITD-expressing cell lines and AML patient blasts treated with the FLT3 inhibitor gilteritinib and/or the Pim inhibitors AZD1208 or TP-3654. The data are consistent with c-Myc T58 and Mcl-1 S159 phosphorylation by activated GSK-3β as the mechanism of action of gilteritinib and Pim inhibitor combination treatment, further supporting GSK-3β activation as a therapeutic strategy in FLT3-ITD AML.  .
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • MCL1 (Myeloid cell leukemia 1) • PIM1 (Pim-1 Proto-Oncogene)
|
MYC expression • MCL1 expression • FLT3-ITD expression • MCL1 S159A
|
Xospata (gilteritinib) • AZD1208 • TP-3654
4ms
GNF-7, a novel FLT3 inhibitor, overcomes drug resistance for the treatment of FLT3‑ITD acute myeloid leukemia. (PubMed, Cancer Cell Int)
Our results show that GNF-7 is a potent FLT3-ITD inhibitor and may become a promising lead compound applied for treating some of the clinically drug resistant patients.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
|
FLT3-ITD mutation • FLT3 mutation • FLT3 F691L • FLT3 expression • FLT3-ITD expression • FLT3-ITD mutation + FLT3 F691L
|
Xospata (gilteritinib) • Vanflyta (quizartinib)
4ms
N-(3-Methoxyphenyl)-6-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-amine is an inhibitor of the FLT3-ITD and BCR-ABL pathways, and potently inhibits FLT3-ITD/D835Y and FLT3-ITD/F691L secondary mutants. (PubMed, Bioorg Chem)
Studies indicate that it mediates proapoptotic effects on cells by inhibiting FLT3 and BCR-ABL pathways, and other possible targets. Compound 1 is more potent against FLT3-ITD than BCR-ABL, and it may have other possible targets; however, compound 1 is first step for further optimization for the development of a balanced FLT3-ITD/BCR-ABL dual inhibitor for the treatment of relapsed FLT3-ITD mutated AML with multiple secondary clinical resistant subtypes such as FLT3-ITD/D835Y, FLT3-ITD/F691L, and cells co-expressing FLT3-ITD and BCR-ABL.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase)
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FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 expression • FLT3-ITD expression
5ms
The ELN 2022 Risk Stratification Has No Impact on the Dismal Prognosis of Patients with Acute Undifferentiated Leukemia (ASH 2023)
The unique subtype of AUL is associated with a particularly adverse risk genotype, irrespective of known prognostic determinants, as in the 2022 ELN classification.
Clinical
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NPM1 (Nucleophosmin 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • CD123 (Interleukin 3 Receptor Subunit Alpha) • CD34 (CD34 molecule) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • CD36 (thrombospondin receptor) • NCAM1 (Neural cell adhesion molecule 1) • CD14 (CD14 Molecule) • CD7 (CD7 Molecule) • IL3RA (Interleukin 3 Receptor Subunit Alpha) • ITGAX (Integrin Subunit Alpha X)
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TP53 mutation • FLT3-ITD mutation • NPM1 mutation • RUNX1 mutation • JAK2 mutation • NCAM1 expression • FLT3 expression • FLT3-ITD expression
5ms
Clinico-Genomic Characterization of AML Patients Based on IL2RA (CD25) Expression Uncovers an Association with Stem Cell Signatures and FLT3-ITD Status and Informs Drug Combinations (ASH 2023)
Ex vivo drug sensitivity analyses support combinations of CD25-targeting agents with FLT3 inhibitors, as well as venetoclax. Additional work to evaluate these and other combinations using functional assays is warranted.
Clinical
|
FLT3 (Fms-related tyrosine kinase 3) • IL2RA (Interleukin 2 receptor, alpha) • ISG20 (Interferon Stimulated Exonuclease Gene 20)
|
IL2RA expression • FLT3 expression • FLT3-ITD expression
|
Venclexta (venetoclax)
5ms
In Vivo Antileukemic Activity of Ost-01 in Acute Myeloid Leukemia (AML): A Novel Natural Product (NP) from Baccharis Coridifolia (ASH 2023)
Compared with OST-01 alone or V, combination of OST-01 and the BCL-2 inhibitor, venetoclax (VEN) demonstrated a synergistic activity on AML cell lines and primary blasts (max synergy score: 28.16), and prolonged survival of MllPTD/WT/Flt3ITD/ITD AML mice (VEN/OST vs OST and VEN, median: 156 vs 123 and 95 days, p=0.0003 and p<0.0001; secondary transplant median: 105 vs 58 and 31 days, p<0.0001 and p<0.0001, respectively) and CM AML mice (VEN/OST vs OST and VEN, median: 85 vs 70 and 58 days, p=0.0005 and p<0.0001; secondary transplant median: 95 vs 62.5 and 48 days, p=0.0003 and p<0.0001, respectively). To date, no preclinical toxicity has been observed. We concluded that OST-01 is a non-toxic, potentially new therapy for AML; translation from the bench to the bedside is underway.
Preclinical • IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • CD38 (CD38 Molecule) • CD34 (CD34 molecule) • NCL (Nucleolin)
|
FLT3 expression • FLT3-ITD expression • MLL-PTD
|
Venclexta (venetoclax)
5ms
The interplay of FLT3 and CXCR4 in acute myeloid leukemia: an ongoing debate. (PubMed, Front Oncol)
Taken together, the current research status is not sufficient to answer the question whether FLT3 and CXCR4 act together or independently in leukemia progression. Systematic analyses in model cell systems are needed to understand the interplay between FLT3 and CXCR4, since this knowledge could lead to the development of more effective treatment strategies for AML patients.
Review • Journal
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FLT3 (Fms-related tyrosine kinase 3) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CXCL12 (C-X-C Motif Chemokine Ligand 12)
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FLT3 mutation • FLT3-ITD expression • CXCR4 expression
7ms
Preliminary study on the regulation of acute myeloid leukemia by FLT3 gene expression (PubMed, Zhonghua Yi Xue Yi Chuan Xue Za Zhi)
Over-expression of FLT3 may influence the course of AML by promoting the proliferation of leukemia cells and inhibiting their apoptosis, which in turn may affect the prognosis of patients and serve as a negative prognostic factor for AML.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • BAK1 (BCL2 Antagonist/Killer 1)
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FLT3 overexpression • FLT3 expression • FLT3-ITD expression
7ms
Inhibition of FLT3-ITD Kinase in Acute Myeloid Leukemia by New Imidazo[1,2-b]pyridazine Derivatives Identified by Scaffold Hopping. (PubMed, J Med Chem)
In vitro experiments confirmed suppression of FLT3 downstream signaling pathways. Finally, the treatment of MV4-11 xenograft-bearing mice with 34f at doses of 5 and 10 mg/kg markedly blocked tumor growth without any adverse effects.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 D835 • FLT3 expression • FLT3-ITD expression
8ms
Combination strategies to overcome drug resistance in FLT acute myeloid leukaemia. (PubMed, Cancer Cell Int)
This study suggests that a multi-targeted intervention involving a CDK4/6 inhibitor with a FLT3 inhibitor or a pan-PI3K inhibitor might be a valuable therapeutic strategy for AML to overcome drug resistance. Moreover, many patients cannot tolerate high doses of the drugs that were studied (quizartinib, palbociclib and PI3K inhibitors) for longer periods, and it is therefore of high significance that the drugs act synergistically and lower doses can be used.
Journal
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3 expression • FLT3-ITD expression
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Ibrance (palbociclib) • Piqray (alpelisib) • Verzenio (abemaciclib) • Xospata (gilteritinib) • Vanflyta (quizartinib) • Aliqopa (copanlisib) • Zydelig (idelalisib) • Copiktra (duvelisib)
11ms
THE PROGNOSTIC SIGNIFICANCE OF BCAT1 ON NPM1+FLT3-ITD+ AML PATIENTS AND RELATED MOLECULAR MECHANISMS (EHA 2023)
In the Nanostring cohort, RNA-Seq cohort, GSE6891, GSE10358, GSE15434, Beat-AML and TCGA-AML, a total of seven cohorts, BCAT1 was highly expressed in the NPM1+ FLT3-ITD+ group. In the RNA-Seq cohort and Nanostring cohort of Peking University Institute of Hematology, BCAT1 expression levels could effectively predict the prognosis of NPM1+ FLT3-ITD+AML patients, and the ability of BCAT1 transcript levels to predict the prognosis of NPM1+ITD+AML patients was superior to FLT3-ITD allelic ration. MV411 and MOLM13 cell lines were treated with AC220 respectively and BCAT1 expression was found to be significantly down-regulated at the mRNA level and the protein level.
Clinical
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • BCAT1 (Branched Chain Amino Acid Transaminase 1 )
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FLT3-ITD mutation • NPM1 mutation • MYC expression • FLT3 expression • FLT3-ITD expression • NPM1 expression • BCAT1 expression
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Vanflyta (quizartinib)
12ms
Antileukemic effect of cyclin-dependent kinase 7 inhibitor; YPN-005 combined with FLT3 inhibitor in FMS-tyrosine kinase 3 -mutated acute myeloid leukemia (ICKSH 2023)
FLT3-TKIs include midostaurin, gilteritinib, and quizartinib. These results provide preclinical evidence of combined treatment of YPN-005 and FLT3 inhibitor for therapeutic strategies for FLT3-mutated AML. Keyword : FLT3-ITD, CDK7 inhibitor, Mitochondrial dysfunction, Apoptosis
PARP Biomarker
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FLT3 (Fms-related tyrosine kinase 3) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • MCL1 (Myeloid cell leukemia 1) • CASP3 (Caspase 3) • CDK7 (Cyclin Dependent Kinase 7) • ANXA5 (Annexin A5)
|
FLT3-ITD mutation • FLT3 mutation • MYC expression • MCL1 expression • FLT3-ITD expression
|
Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • YPN-005
1year
Clinical
|
FLT3 (Fms-related tyrosine kinase 3) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor)
|
MYC expression • FLT3 expression • FLT3-ITD expression
1year
HX301 (ON1232580) a novel kinase inhibitor with potent activity against CSF1R and FLT3, shows strong anti-AML activity in defined preclinical models (AACR 2023)
HX301 also suppressed AM7577 growth, likely due to the suppression of FLT3-ITD activity since we previously reported FLT3-ITD being the driver mutation in this model which responded to AC220, a FLT3 TKi...Further preclinical/translational studies are being conducted in order to reveal predictive biomarkers, in addition to FLT3 mutation and CSF1R expression/mutations. We believe that HX301 could be a potential candidate for treating subset of AML, warranting further clinical investigation.
Preclinical
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FLT3 (Fms-related tyrosine kinase 3) • CSF1R (Colony stimulating factor 1 receptor)
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FLT3-ITD mutation • FLT3 mutation • FLT3 wild-type • FLT3 expression • FLT3-ITD expression
|
Vanflyta (quizartinib) • narazaciclib (ON 123300)
1year
Hsa_circ_0015278 Regulates FLT3-ITD AML Progression via Ferroptosis-Related Genes. (PubMed, Cancers (Basel))
qRT-PCR results confirmed that has_circ_0015278 was significantly overexpressed in FLT3-ITD mutant-type AML. In summary, we constructed the hsa_circ_0015278/miRNAs/FerRGs signaling axis, which provides new insight into the pathogenesis and therapeutic targets of AML with FLT3-ITD mutation.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • MAPK3 (Mitogen-Activated Protein Kinase 3)
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FLT3-ITD mutation • FLT3 expression • FLT3-ITD expression
over1year
Synthesis and biological activity evaluation of novel 3,5,7-trisubstituted pyrazolo[1,5-a]pyrimidines. (PubMed, Bioorg Med Chem Lett)
Derivative 10b was capable to strongly inhibit all kinases and its selectivity in FLT3-ITD expressing cell lines MOLM13 and MV4-11 was in line with FLT3-ITD inhibition. Further biochemical analyses and molecular docking confirmed FLT3 as a cellular target of 10b.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • CDK2 (Cyclin-dependent kinase 2) • CDK9 (Cyclin Dependent Kinase 9)
|
FLT3 mutation • FLT3-ITD expression
over1year
PRMT5 Inhibition Enhances Elimination of FLT3-ITD AML Stem Cells in Combination with TKI Treatment (ASH 2022)
The combination of GSK-591 or LLY-283 with either of the FLT3 TKIs Quizartinib or Giltertinib resulted in synergistically enhanced inhibition of FLT3-ITD+ MOLM-13 and MV4-11 AML cells, compared to TKI or PRMT5 inhibitor alone. An epigenetic probe screen identified PRMT5 as a key regulator of FLT3-ITD AML cell viability. We show an important role for PRMT5 in maintenance of murine and human FLT3-ITD AML stem cells and in their persistence following FLT3 TKI treatment. Treatment with a PRMT5 inhibitor in combination with a FLT3 TKI could be a promising approach to enhance elimination of FLT3-ITD AML stem cells.
Combination therapy • IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • TET2 (Tet Methylcytosine Dioxygenase 2) • CD38 (CD38 Molecule) • CD34 (CD34 molecule) • PRMT5 (Protein Arginine Methyltransferase 5) • PRMT1 (Protein Arginine Methyltransferase 1) • GLI2 (GLI Family Zinc Finger 2) • PRMT7 (Protein Arginine Methyltransferase 7) • ANXA5 (Annexin A5)
|
FLT3-ITD mutation • FLT3 expression • FLT3-ITD expression • TET2 deletion
|
Vanflyta (quizartinib) • GSK591 • LLY-283
over1year
A Comparison of Outcomes in Patients with Secondary Acute Promyelocytic Leukemia (APL) and De Novo APL – a Case-Match Retrospective Analysis of Polish Adult Leukemia Group (PALG) (ASH 2022)
Conclusions The results of this case-matched study are in line with the previous suggestions that outcomes of pts with sAPL may be similar to those with the disease de novo. We also conclude that there is no difference in the clinical and biological presentation of sAPL and de novo APL at the time of diagnosis.
Retrospective data
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FLT3 (Fms-related tyrosine kinase 3)
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FLT3-ITD expression
over1year
Rational polypharmacological targeting of FLT3, JAK2, ABL, and ERK1 suppresses the adaptive resistance to FLT3 inhibitors in AML. (PubMed, Blood Adv)
Pluripotin treatment curbed the progression of AML in multiple in vivo models including patient-derived primary AML cells in mouse xenotransplants. As a proof of concept, we demonstrate that targeted polypharmacological inhibition of key signaling nodes driving adaptive resistance can provide a durable response.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • JAK2 (Janus kinase 2)
|
FLT3-ITD mutation • FLT3 F691L • FLT3 expression • FLT3-ITD expression
over1year
FLT3-ITD Expression as a Potential Biomarker for the Assessment of Treatment Response in Patients with Acute Myeloid Leukemia. (PubMed, Cancers (Basel))
With regard to the post-FLT3i follow-up, FLT3-ITD expression was reduced after the first FLT3i cycle when the treatment was effective, whereas it was not reduced in refractory patients. FLT3-ITD expression could be a useful additional biomarker at diagnosis and for the assessment of MRD after allo-HSCT and FLT3i in AML.
Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3-ITD mutation • FLT3-ITD expression
over1year
"FLipping" the Story: FLT3-Mutated Acute Myeloid Leukemia and the Evolving Role of FLT3 Inhibitors. (PubMed, Cancers (Basel))
In April 2017, midostaurin became both the first FLT3 inhibitor and the first targeted therapy of any kind in AML to be approved by the US FDA. The use of FLT3 inhibitors has continued to grow as clinical trials continue to demonstrate the efficacy of this class of agents, with an expanding number available for use as both experimental standard-of-care usage. This review examines the biology of FLT3 and its downstream pathways, the mechanism of FLT3 inhibition, the development of the FLT3 inhibitors as a class and uses of the agents currently available clinically, and the mechanisms by which resistance to FLT3 inhibition may both develop and be overcome.
Review • Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3-ITD mutation • FLT3 mutation • FLT3 expression • FLT3-ITD expression
|
sorafenib • Xospata (gilteritinib) • Rydapt (midostaurin) • Vanflyta (quizartinib) • crenolanib (ARO-002)
over1year
Impact of HOXB4 and PRDM16 Gene Expressions on Prognosis and Treatment Response in Acute Myeloid Leukemia Patients. (PubMed, Pharmgenomics Pers Med)
Further larger study should be conducted to verify that high PRDM16 and low HOXB4 gene expressions could be used as a poor prognostic predictor for AML. The correlation between PRDM16 and HOXB4 gene expressions and FLT3-ITD and NPM1 exon 12 mutations might have a role on CR, relapse, OS, and, however, this should be clarified in analysis with a larger number of samples.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • HOXB4 (Homeobox B4) • PRDM16 (PR/SET Domain 16)
|
FLT3-ITD mutation • NPM1 mutation • FLT3 expression • FLT3-ITD expression
almost2years
TRANSCRIPTIONAL AND TRANSLATIONAL SIGNATURES OF TRIPLE MUTATED DNMT3AKO/FLT3ITD/NPM1C MICE SHOW ALTERED RNAS PROCESSING AND CELL CYCLE PROGRESSION (EHA 2022)
Conclusion The leukemic DNMT3A KO / FLT3 ITD / NPM1 c genotype is characterized by unique transcriptional and translational signatures. The information about deregulated pathways and altered protein synthesis establishes the rational basis for designing new therapeutic approaches in this poor prognosis AML genotype.
Preclinical
|
TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • HOXA9 (Homeobox A9) • RAC1 (Rac Family Small GTPase 1)
|
FLT3-ITD mutation • FLT3 mutation • NPM1 mutation • DNMT3A mutation • DNMT3A mutation + NPM1 mutation • FLT3-ITD expression
almost2years
Molecular mechanisms by which splice modulator GEX1A inhibits leukaemia development and progression. (PubMed, Br J Cancer)
Our study suggests that GEX1A is a potent anti-leukaemic agent in combination with BCL-xL inhibitors, which targets leukaemic blasts and leukaemia stem cells through distinct mechanisms.
Journal • IO biomarker
|
FLT3 (Fms-related tyrosine kinase 3) • MCL1 (Myeloid cell leukemia 1) • BCL2L1 (BCL2-like 1)
|
BCL2 expression • FLT3 expression • FLT3-ITD expression
2years
Identification of 2-Aminopyrimidine Derivatives as FLT3 Kinase Inhibitors with High Selectivity over c-KIT. (PubMed, J Med Chem)
No clear myelosuppression was observed in the treated group of 36 in the MPO strain of zebrafish, even at 10 μM. In summary, our data demonstrated that 36 may represent a promising candidate for the treatment of FLT3 mutant AML.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • KIT (KIT proto-oncogene, receptor tyrosine kinase)
|
FLT3-ITD mutation • FLT3 mutation • FLT3 D835Y • FLT3 F691L • FLT3 D835 • FLT3 D835V • FLT3 expression • FLT3-ITD expression
2years
Concurrent treatment with Pim kinase inhibitor enhances efficacy of FLT3 inhibitors in AML with FLT3-ITD through GSK-3βactivation and GSK-3β-mediated enhanced proteasomal degradation of c-Myc and Mcl-1 (AACR 2022)
The serine/threonine kinase GSK-3β regulates c-Myc and Mcl-1 protein via phosphorylation at T58 and S159, respectively; we hypothesized downregulation of both proteins by combination treatment through phosphorylation by GSK-3β. FLT3-ITD cells lines (Ba/F3-ITD, MV4-11, and MOLM-14) and primary FLT3-ITD AML patient blasts were cultured with the pan-Pim kinase inhibitor AZD1208, the FLT3 inhibitors gilteritinib or quizartinib and the GSK-3β inhibitor TCG-24...To measure protein half-lives, cells were pretreated with cycloheximide with and without the proteasome inhibitor MG-132... Pim inhibitors enhance efficacy of FLT3 inhibitors via GSK-3β activation and GSK-3β-mediated enhanced proteasomal degradation of c-Myc and Mcl-1, highlighting GSK-3β as a key target in cells with FLT3-ITD.
Clinical
|
FLT3 (Fms-related tyrosine kinase 3) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • MCL1 (Myeloid cell leukemia 1) • PIM1 (Pim-1 Proto-Oncogene)
|
FLT3-ITD expression • MCL1 S159A
|
Xospata (gilteritinib) • Vanflyta (quizartinib) • AZD1208 • MG132
2years
FLT3-ITD allelic ratio and HLF expression predict FLT3 inhibitor efficacy in adult AML. (PubMed, Sci Rep)
The retrospective analysis of AML patients treated with FLT3 inhibitor sorafenib showed that patients with high HLF expression and ITD-AR had better clinical response to therapy compared to those with low ITD-AR and HLF expression. Thus, our findings suggest that FLT3 ITD-AR together with increased HLF expression play a role in variable FLT3 inhibitor responses observed in FLT3-ITD AML patients.
Clinical • Retrospective data • Journal
|
FLT3 (Fms-related tyrosine kinase 3)
|
FLT3-ITD mutation • FLT3 expression • FLT3-ITD expression • HLF overexpression + FLT3-ITD mutation
|
sorafenib
over2years
Modulation of FLT3-ITD Localization and Targeting of Distinct Downstream Signaling Pathways as Potential Strategies to Overcome FLT3-Inhibitor Resistance. (PubMed, Cells)
The allocation of FLT3-ITD to different cellular compartments and targeting distinct downstream signaling pathways by combined treatment with N-glycosylation and HSP90 inhibitors or VPA and rapamycin might represent new therapeutic strategies to overcome resistance towards tyrosine kinase inhibitors in FLT3-ITD-positive AML. The treatment approaches addressing N-glycosylation of FLT3-ITD appear to depend on patient-specific FLT3-ITD sequences, potentially affecting the efficacy of such pharmacological strategies.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • CALR (Calreticulin)
|
FLT3-ITD expression
|
sirolimus
over2years
New Anti-Cancer Drug Compounds to Treat FLT-3 Mutated Leukemia (ASH 2021)
Different drugs are used to treat AML such as midostaurin, azacytidine, and daunorubicin. Further studies will be necessary to understand more the molecular mechanism affected by the compound A and/or B in the FLT-3 pathway. The compounds A and B demonstrate potential in treatment of AML expressing FLT-ITD.
PARP Biomarker
|
FLT3 (Fms-related tyrosine kinase 3) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CASP3 (Caspase 3) • CASP7 (Caspase 7) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
|
FLT3-ITD mutation • FLT3 mutation • FLT3 expression • FLT3-ITD expression
|
azacitidine • Rydapt (midostaurin) • daunorubicin
over2years
Momelotinib is a highly potent inhibitor of FLT3-mutant AML. (PubMed, Blood Adv)
Altogether, these data provide evidence that momelotinib is an effective type-1 dual JAK2/FLT3 inhibitor and may offer an alternative to gilteritinib. Its ability to impede the resistance conferred by growth factor signaling and activation loop mutants suggests that momelotinib treatment could provide a deeper and durable response; thus, warrants its clinical evaluation.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • MYC (V-myc avian myelocytomatosis viral oncogene homolog)
|
FLT3-ITD mutation • FLT3 mutation • MYC expression • FLT3 D835 • FLT3 expression • FLT3-ITD expression
|
Xospata (gilteritinib) • Ojjaara (momelotinib)
over2years
Aryl Hydrocarbon Receptor (AHR) Gene Expression in AML Is Associated with FLT3-ITD+ AML and HLA-E Induced Immune Resistance Reversed By Ik-364 (ASH 2021)
The highest and lowest 10% expression levels of AHR in all samples in Beat AML were evaluated for mutation profiles. Ranking the top 18 mutations based on frequency we found an enrichment of FLT3 mutations in the high AHR expression group compared to the lower expression group (Figure 1A). ELN risk did not correlate with AHR expression however FAB classification M0/M1 and M4/M5 monocytic subtypes had higher AHR expression than M3 FAB subtype (Figure 2A).
PD(L)-1 Biomarker • IO biomarker
|
FLT3 (Fms-related tyrosine kinase 3) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • CASP3 (Caspase 3) • CD14 (CD14 Molecule) • MAFB (MAF BZIP Transcription Factor B) • AHR (Aryl hydrocarbon receptor) • CASP7 (Caspase 7) • CD86 (CD86 Molecule)
|
FLT3-ITD mutation • FLT3 mutation • FLT3-ITD expression • AHR expression
over2years
Pim kinase inhibitor co-treatment decreases alternative non-homologous end-joining DNA repair and genomic instability induced by topoisomerase 2 inhibitors in cells with FLT3 internal tandem duplication. (PubMed, Oncotarget)
TOP2 inhibitor treatment increased chromosome breaks in metaphase spreads in FLT3-ITD-expressing cells, and AZD1208 co-treatment abrogated these increases. Thus Pim kinase inhibitor co-treatment both enhances TOP2 inhibitor cytotoxicity and decreases TOP2 inhibitor-induced genomic instability in cells with FLT3-ITD.
Journal
|
FLT3 (Fms-related tyrosine kinase 3) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • PIM1 (Pim-1 Proto-Oncogene) • XRCC1 (X-Ray Repair Cross Complementing 1)
|
MYC overexpression • MYC expression • FLT3-ITD expression
|
AZD1208
over2years
Maturation State-Specific Alternative Splicing in FLT3-ITD and NPM1 Mutated AML. (PubMed, Cancers (Basel))
Interestingly, we observed functional divergence between alternatively spliced and differentially expressed genes in FLT3-ITD+/NPM1+ samples in all analyzed FAB types, with differential expression affecting genes involved in hematopoietic differentiation. Altogether, these observations indicate that concomitant FLT3-ITD and mutated NPM1 are associated with the maturation state-specific differential splicing of genes with potential oncogenic relevance.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1)
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FLT3-ITD mutation • NPM1 mutation • FLT3‐ITD  + NPM1 mutation • FLT3 expression • FLT3-ITD expression