GetITD for FLT3-ITD-based MRD monitoring in AML.
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ABSTRACT:
SUBMITTER: Blatte TJ
PROVIDER: S-EPMC8075860 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The FLT3-ITD mutation is one of the most prevalent oncogenic mutations in AML. Several FLT3 kinase inhibitors have shown impressive activity in clinical evaluation, however clinical responses are usually transient and clinical effects are rapidly lost due to drug resistance. One of the resistance mechanisms in the AML refractory patients involves FLT3-ligand induced reactivation of AKT and/or ERK signaling via FLT3 wt kinase. Via a screen of numerous AKT kinase inhibitors, we identified the well-established orally available AKT inhibitor, A674563, as a dual suppressor of AKT and FLT3-ITD. A674563 suppressed FLT3-ITD positive AML both in vitro and in vivo. More importantly, compared to other FLT3 inhibitors, A674563 is able to overcome FLT3 ligand-induced drug resistance through simultaneous inhibition of FLT3-ITD- and AKT-mediated signaling. Our findings suggest that A674563 might be a potential drug candidate for overcoming FLT3 ligand-mediated drug resistance in FLT3-ITD positive AML.
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Project description:Acute myelogenous leukemia (AML) is often associated with activating mutations in the receptor tyrosine kinase, Flt3, including internal tandem duplications (ITDs) within the regulatory juxtamembrane region. Previous studies have linked Flt3-ITD to the activation of the Fes protein tyrosine kinase in AML, and RNAi-knockdown studies suggest that Fes may be required for Flt3 function. In this study, we tested Fes inhibitors from three different chemical classes for their growth-suppressive activity against Flt3-ITD+ myeloid leukemia cell lines (MV4-11, MOLM-13 and MOLM-14) vs. myeloid cells with wild-type Flt3 (THP-1). All Fes inhibitors selectively inhibited the growth of Flt3-ITD+ AML cells, with IC50 values for diaminopyrimidine and pyrrolopyridine inhibitors ranging from 19 to 166 nM. In contrast, a pyrazolopyrimidine inhibitor was less potent in Flt3-ITD+ AML cells, with IC50 values in the 1.0 μM range. In vitro kinase assays showed that the most potent inhibitors of Flt3-ITD+ AML cell proliferation blocked both Fes and Flt3-ITD kinase activity, while the pyrazolopyrimidine was more selective for Fes vs. Flt3-ITD. All three inhibitors induced significant apoptosis in Flt3-ITD+ AML cells, with potency equivalent to or greater than the established Flt3-ITD inhibitor, tandutinib. Transformation of TF-1 cells with Flt3-ITD resulted in constitutive activation of endogenous Fes, and rendered the cells highly sensitive to all three Fes inhibitors with IC50 values in the 30-500 nM range. The pyrrolopyridine compound also induced apoptotic responses in patient-derived Flt3-ITD+ AML bone marrow cells but not in normal bone marrow mononuclear cells. These results demonstrate that Fes kinase activity contributes to Flt3-ITD signaling in AML, and suggests that dual inhibition of both Flt3 and Fes may provide a therapeutic advantage for the treatment of Flt3-ITD+ AML.
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| S-EPMC5053879 | biostudies-literature
Project description:FLT3 internal tandem duplication (FLT3/ITD) is a common somatic mutation in acute myeloid leukemia (AML) with significant variation in the position, length, and number of duplications of the FLT3 gene. We evaluated these physical characteristics in FLT3/ITD-positive patients who were treated on CCG-2941/2961 and correlated them with clinical outcome. Fiftynine of 77 FLT3/ITD-positive patients (77%) had a single ITD, 16 (21%) had 2 ITDs, and 2 (3%) had 3 ITDs. The length of the duplicated region varied from 6 to 51 amino acids, and in all cases amino acid residues Y591-Y597 were duplicated. Structural analysis demonstrated that Y591-Y597 encodes the switch and zipper regions of the juxtamembrane domain of FLT3. In addition, 24 of 77 patients (31%) had duplication of the critical STAT5 docking sites Y589/591. Patients with longer ITDs had a worse relapse-free survival (19% vs 51%, P = .035), while the presence of more than 1 ITD was not clinically significant. Physical characteristics including the length of FLT3/ITD may influence FLT3 activation state by altering its structure and may impact response to therapy.
| S-EPMC2384125 | biostudies-literature
Project description:AML with the FLT3-ITD mutation seriously threatens human health. The mechanism by which circRNAs regulate the pathogenesis of FLT3-ITD mutant-type AML through ferroptosis-related genes (FerRGs) remains unclear. Differentially expressed circRNAs and mRNAs were identified from multiple integrated data sources. The target miRNAs and mRNAs of the circRNAs were predicted using various databases. The PPI network, ceRNA regulatory network, GO, and KEGG enrichment analyses were performed. The "survival" and the "pROC" R packages were used for K-M and ROC analysis, respectively. GSEA, immune infiltration analysis, and clinical subgroup analysis were performed. Finally, circRNAs were validated by Sanger sequencing and qRT-PCR. In our study, 77 DECircs-1 and 690 DECircs-2 were identified. Subsequently, 11 co-up-regulated DECircs were obtained by intersecting DECircs-1 and DECircs-2. The target miRNAs of the circRNAs were screened by CircInteractome, circbank, and circAtlas. Utilizing TargetScan, ENCORI, and miRWalk, the target mRNAs of the miRNAs were uncovered. Ultimately, 73 FerRGs were obtained, and the ceRNA regulatory network was constructed. Furthermore, MAPK3 and CD44 were significantly associated with prognosis. 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.
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| S-EPMC10169656 | biostudies-literature
Project description:A hallmark of cancer is the disruption of differentiation within tumor cells. Internal tandem duplication mutations of the FLT3 kinase (FLT3/ITD) occur commonly in acute myeloid leukemia (AML) and are associated with poor survival, leading to efforts to develop FLT3 kinase inhibitors. However, FLT3 inhibitors have thus far met with limited success, inducing only a clearance of peripheral blasts with minimal BM responses. Quizartinib is a novel potent and selective FLT3 inhibitor currently being studied in clinical trials. In 13 of 14 FLT3/ITD AML patients with normal karyotype treated with quizartinib, we observed terminal myeloid differentiation of BM blasts in association with a clinical differentiation syndrome. The single patient whose blasts failed to differentiate had a preexisting C/EBP? mutation and another developed a C/EBP? mutation at disease progression, suggesting a mechanism of resistance to FLT3 inhibition. In vitro, in primary blasts cocultured with human BM stroma, FLT3 inhibition with quizartinib induced cell-cycle arrest and differentiation rather than apoptosis. The present study is the first description of terminal differentiation of cancer cells in patients treated with a tyrosine kinase inhibitor. These data highlight the importance of the differentiation block in the patho-genesis of AML.
| S-EPMC3501718 | biostudies-literature
Project description:Acute myeloid leukemia (AML) is a heterogeneous disease with dismal response warranting the need for enhancing our understanding of AML biology. One prognostic feature associated with inferior response is the presence of activating mutations in FMS-like tyrosine kinase 3 (FLT3) especially occurrence of internal tandem duplication (FLT3-ITD). Although poorly understood, differential metabolic and signaling pathways associated with FLT3-ITD might contribute towards the observed poor prognosis. We performed a non-targeted global metabolic profiling of matched cell and plasma samples obtained at diagnosis to establish metabolic differences within FLT3-ITD and FLT3-WT pediatric AML. Metabolomic profiling by Ultra-High Performance-Liquid-Chromatography-Mass Spectrometry identified differential abundance of 21 known metabolites in plasma and 33 known metabolites in leukemic cells by FLT3 status. These metabolic features mapped to pathways of significant biological importance. Of interest were metabolites with roles in cancer, cell progression and involvement in purine metabolism and biosynthesis, cysteine/methionine metabolism, tryptophan metabolism, carnitine mediated fatty acid oxidation, and lysophospholipid metabolism. Although validation in a larger cohort is required, our results for the first time investigated global metabolic profile in FLT3-ITD AML.
| S-EPMC5882915 | biostudies-literature
Project description:FLT3 internal tandem duplication (FLT3-ITD) is a frequent mutation in acute myeloid leukemia (AML) and remains a strong prognostic factor due to high rate of disease recurrence. Several FLT3-targeted agents have been developed, but determinants of variable responses to these agents remain understudied. Here, we investigated the role FLT3-ITD allelic ratio (ITD-AR), ITD length, and associated gene expression signatures on FLT3 inhibitor response in adult AML. We performed fragment analysis, ex vivo drug testing, and next generation sequencing (RNA, exome) to 119 samples from 87 AML patients and 13 healthy bone marrow controls. We found that ex vivo response to FLT3 inhibitors is significantly associated with ITD-AR, but not with ITD length. Interestingly, we found that the HLF gene is overexpressed in FLT3-ITD+ AML and associated with ITD-AR. 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.
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