Acute Myeloid Leukemia (AML) is a complex hematologic malignancy characterized by the rapid proliferation of abnormal myeloid precursor cells. The FMS-like tyrosine kinase 3 (FLT3), a receptor tyrosine kinase, plays a pivotal role in regulating cell survival, proliferation, and differentiation within the hematopoietic system. Mutations in FLT3, particularly internal tandem duplications (ITDs) and point mutations within the tyrosine kinase domain (TKD), are prevalent in AML and are associated with poor prognosis and increased risk of relapse. The development of targeted therapies has revolutionized the landscape of cancer treatment by focusing on the inhibition of kinase signalling. Small-molecule inhibitors designed to selectively target receptor tyrosine kinases, such as PLX3397, have shown promising results in preclinical studies and early phase clinical trials. PLX3397 exerts its inhibitory effects by targeting CSF1R and KIT, leading to the disruption of receptor tyrosine kinase signalling cascades, suppression of leukemic cell growth, and induction of apoptosis. This study emphasizes the significance of FLT3 as a receptor tyrosine kinase as a therapeutic target for PLX3397. After evaluating the usefulness of PLX3397 as an enzyme inhibitor using ADMET prediction, PLX3397 was prepared for molecular docking in the FLT3 crystal structure (PDB: 4XUF). A molecular dynamics simulation was performed on PLX3397 to evaluate its binding affinity and protein stability in a simulated physiological environment. In conclusion, targeting FLT3 as a receptor tyrosine kinase with PLX3397 represents a promising therapeutic strategy for improving outcomes in patients with FLT3-mutated AML. Further clinical investigations are warranted to validate the efficacy and safety of PLX3397 and to optimize treatment strategies for AML patients based on the FLT3 mutational status.

Acute myeloid leukemia (AML) has a poor survival rate for both pediatric and adult patients due to its frequent relapse. To elucidate the bioenergetic principle underlying AML relapse, we investigated the transcriptional regulation of mitochondrial-nuclear dual genomes responsible for metabolic plasticity in treatment-resistant blasts. Both the gain and loss of function results demonstrated that NFκB2, a noncanonical transcription factor (TF) of the NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) family, can control the expression of TFAM (mitochondrial transcription factor A), which is known to be essential for metabolic biogenesis. Furthermore, genetic tracking and promoter assays revealed that NFκB2 is in the mitochondria and can bind the specific \"TTGGGGGGTG\" region of the regulatory D-loop domain to activate the light-strand promoter (LSP) and heavy-strand promoter 1 (HSP1), promoters of the mitochondrial genome. Based on our discovery of NFκB2\'s novel function of regulating mitochondrial-nuclear dual genomes, we explored a novel triplet therapy including inhibitors of NFκB2, tyrosine kinase, and mitochondrial ATP synthase that effectively eliminated primary AML blasts with mutations of the FMS-related receptor tyrosine kinase 3 (FLT3) and displayed minimum toxicity to control cells ex vivo. As such, effective treatments for AML must include strong inhibitory actions on the dual genomes mediating metabolic plasticity to improve leukemia prognosis.

Corilagin (CLG) has antitumor activities in certain human malignant cancers. Herein, the effects and mechanisms of CLG on osteosarcoma (OS) were investigated. OS cell viability and proliferation were detected by MTT and colony formation assay. Cell cycle and apoptosis were examined using flow cytometry. The interaction between TRAF6 and FLT3 was investigated using a co-immunoprecipitation assay. Results demonstrated that CLG treatment inhibited OS cell viability and proliferation but promoted OS cell autophagy and apoptosis in a concentration-dependent manner. Mechanically, CLG inhibited TRAF6-mediated FLT3 ubiquitination degradation. TRAF6 overexpression abolished the effects of CLG on OS cell proliferation, autophagy, and apoptosis. Finally, CLG administration inhibited OS tumor growth in mice by inducing autophagy-dependent apoptosis. Taken together, CLG inhibited OS progression by facilitating mTOR/ULK1 pathway-mediated autophagy through inhibiting TRAF6-mediated FLT3 ubiquitination, which indicated that CLG was a promising candidate for the treatment of OS.

BACKGROUND: Approximately 25-30% of patients with acute myeloid leukemia (AML) have FMS-like receptor tyrosine kinase-3 (FLT3) mutations that contribute to disease progression and poor prognosis. Prolonged exposure to FLT3 tyrosine kinase inhibitors (TKIs) often results in limited clinical responses due to diverse compensatory survival signals. Therefore, there is an urgent need to elucidate the mechanisms underlying FLT3 TKI resistance. Dysregulated sphingolipid metabolism frequently contributes to cancer progression and a poor therapeutic response. However, its relationship with TKI sensitivity in FLT3-mutated AML remains unknown. Thus, we aimed to assess mechanisms of FLT3 TKI resistance in AML.
METHODS: We performed lipidomics profiling, RNA-seq, qRT-PCR, and enzyme-linked immunosorbent assays to determine potential drivers of sorafenib resistance. FLT3 signaling was inhibited by sorafenib or quizartinib, and SPHK1 was inhibited by using an antagonist or via knockdown. Cell growth and apoptosis were assessed in FLT3-mutated and wild-type AML cell lines via Cell counting kit-8, PI staining, and Annexin-V/7AAD assays. Western blotting and immunofluorescence assays were employed to explore the underlying molecular mechanisms through rescue experiments using SPHK1 overexpression and exogenous S1P, as well as inhibitors of S1P2, β-catenin, PP2A, and GSK3β. Xenograft murine model, patient samples, and publicly available data were analyzed to corroborate our in vitro results.
RESULTS: We demonstrate that long-term sorafenib treatment upregulates SPHK1/sphingosine-1-phosphate (S1P) signaling, which in turn positively modulates β-catenin signaling to counteract TKI-mediated suppression of FLT3-mutated AML cells via the S1P2 receptor. Genetic or pharmacological inhibition of SPHK1 potently enhanced the TKI-mediated inhibition of proliferation and apoptosis induction in FLT3-mutated AML cells in vitro. SPHK1 knockdown enhanced sorafenib efficacy and improved survival of AML-xenografted mice. Mechanistically, targeting the SPHK1/S1P/S1P2 signaling synergizes with FLT3 TKIs to inhibit β-catenin activity by activating the protein phosphatase 2 A (PP2A)-glycogen synthase kinase 3β (GSK3β) pathway.
CONCLUSIONS: These findings establish the sphingolipid metabolic enzyme SPHK1 as a regulator of TKI sensitivity and suggest that combining SPHK1 inhibition with TKIs could be an effective approach for treating FLT3-mutated AML.

Acute myeloid leukemia (AML) is a genetically diverse and challenging malignancy, with mutations in the FLT3 gene being particularly common and deleterious. Gilteritinib, a potent FLT3 inhibitor, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed/refractory AML with FLT3 mutations. Although gilteritinib was developed based on its inhibitory activity against FLT3 kinase, it is important to understand the precise mechanisms of its antileukemic activity in managing drug resistance and discovering biomarkers. This study was designed to elucidate the effect of gilteritinib on the FLT3 expression level. The results showed that gilteritinib induced a dose-dependent decrease in both FLT3 phosphorylation and expression. This reduction was particularly pronounced after 48 h of treatment. The decrease in FLT3 expression was found to be independent of changes in FLT3 mRNA transcription, suggesting post-transcriptional regulatory mechanisms. Further studies were performed in various AML cell lines and cells with both FLT3 wild-type and FLT3 mutant exhibited FLT3 reduction by gilteritinib treatment. In addition, other FLT3 inhibitors were evaluated for their ability to reduce FLT3 expression. Other FLT3 inhibitors, midostaurin, crenolanib, and quizartinib, also reduced FLT3 expression, consistent with the effect of gilteritinib. These findings hold great promise for optimizing gilteritinib treatment in AML patients. However, it is important to recognize that further research is warranted to gain a full understanding of these mechanisms and their clinical implications in the context of FLT3 reduction.

BACKGROUND: Acute myeloid leukemia with normal cytogenetics (CN-AML) represents a heterogeneous group having diverse genetic mutations. Understanding the significance of each of these mutations is necessary. In this study, we evaluated the prognostic role of MN1 expression in adult CN-AML patients.
METHODS: One hundred and sixty-three de-novo adult AML patients were evaluated for MN1 expression by real-time PCR. MN1 expression was correlated with the clinical characteristics of the patients and their outcomes.
RESULTS: Higher MN1 expression was associated with NPM1 wild-type (p<0.0001), CD34 positivity (p=0.006), and lower clinical remission rate (p=0.027). FLT3-ITD and CEBPA mutations had no association with MN1 expression. On survival analysis, a high MN1 expression was associated with poor event-free survival (Hazard Ratio 2.47, 95% Confidence Interval: 1.42-4.3; p<0.0001) and overall survival (Hazard Ratio 4.18, 95% Confidence Interval: 2.17-8.08; p<0.0001). On multivariate analysis, the MN1 copy number emerged as an independent predictor of EFS (p<0.0001) and OS (p<0.0001).
CONCLUSIONS: MN1 expression is an independent predictor of outcome in CN-AML.

UNASSIGNED: Metastatic colon adenocarcinoma presents significant challenges in treatment, particularly when resistant to standard therapies. Precision oncology, guided by multidisciplinary tumor boards (MTBs), offers a promising way for individualized therapeutic approaches. Integration of comprehensive genomic profiling (CGP) and minimal residual disease (MRD) testing strengthens treatment decision-making, yet challenges persist in identifying and overcoming resistance mechanisms. FLT3 amplification can be one of those resistance/escape mechanisms that needs to be targeted.
UNASSIGNED: This case report presents a 58-year-old male diagnosed with metastatic colon adenocarcinoma with liver metastasis, resistant to conventional treatments. Utilizing CGP and MRD testing, our multidisciplinary MTB identified a complex mutational profile, including APC, DAXX, TP53 mutations, and CDK8 and FLT3 amplifications. With a tumor mutational burden of 10 muts/mb and TPS, CPS scores of 0, immunotherapy was considered, employing dual immune checkpoint inhibitors alongside mebendazole and Lenvatinib targeting the WNT and VEGF/angiogenesis pathways. MRD testing revealed early treatment failure. Re-evaluation identified high copied FLT3 amplification (62 copies) as a resistance mechanism, prompting modification to incorporate sorafenib and dual immunotherapy with mebendazole. Subsequent MRD assessments and radiological scans demonstrated a remarkable therapeutic response, with sustained efficacy and absence of detectable residual disease.
UNASSIGNED: This case highlights the successful application of precision oncology principles, facilitated by dynamic MTB-guided treatment strategies. Integration of MRD testing provided early detection of treatment inefficacy, allowing for timely intervention and adaptation of the treatment plan. Additionally, the case highlights the educational value of rare molecular alterations, emphasizing continual learning and refinement of treatment approaches in precision oncology.

Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the abnormal and rapid growth of cells. The mutation of the Fms-like tyrosine kinase 3 ligand gene (FLT3-ITD) represents an important factor in the prognosis of AML. The objective of this study was to determine for the first time the prevalence of FLT3-ITD mutation in west Algerian AML patients. A total of 160 AML patients were genotyped for FLT3-ITD mutation by using polymerase chain reaction. FLT3-ITD mutation was detected in 13% of patients. Mutation rates show no significant difference in the distribution of sex and age. A positive association was found between this mutation and a higher leukocyte and blast cells counts. We also found that the M3 and M5 subtype were the commonest in the FLT3 mutated group. This preliminary study provides first-time prevalence estimates for FLT3-ITD mutation in acute myeloid leukemia patients from the West region of Algeria.

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase expressed in hematopoietic cells. Internal-tandem duplication domain (ITD) mutation and tyrosine kinase domain (TKD) mutation are the two most common mutations in acute myeloid leukemia (AML). Post-translational modifications (PTMs) of FLT3, such as glycosylation and ubiquitination, have been shown to impact various aspects of the protein in both wild-type (WT) and mutant forms of FLT3. In this review, we describe how the glycosylation status of FLT3 affects its subcellular localization, which significantly impacts the activation of downstream signaling, and the impact of specific ubiquitination on FLT3 function and stability, which may be associated with disease progression. Moreover, potential novel therapeutic strategies involving a combination of FLT3 tyrosine kinase inhibitors and drugs targeting glycosylation or ubiquitination are discussed.

Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) primarily expressed in hematopoietic stem cells and dendritic cells (DCs). While FLT3 plays a critical role in the proliferation, development and maintenance of DCs, thus influencing immune responses under both normal and pathological conditions, there also exists some evidence that FLT3+DC may be involved with immune responses in liver transplantation (LT). In this study, results from single-cell sequencing data analysis revealed a clear relationship between FLT3+DCs and Regulatory T cells (Tregs) in liver tissue of LT recipients. In peripheral blood samples of LT patients, levels of FLT3+DCs were decreased post-LT-surgery, while Tregs were increased. In a LT mouse model, levels of FLT3+DCs in the liver and bone marrow exhibited an initial time-dependent decrease followed by an increase after LT surgery. Results as obtained with co-culture experiments using mature BMDCs and CD4+ T cells revealed fluctuations in Tregs in response to FLT3 inhibitors and the FLT3 ligand. These findings suggest that FLT3+DCs could emerge as a novel target for mitigating immune rejection in LT.