rHuman FLt3 Active
- Known as:
- rHuman FLt3 Active
- Catalog number:
- RF00394041-50
- Product Quantity:
- 50
- Category:
- -
- Supplier:
- Agren
- Gene target:
- rHuman FLt3 Active
Related genes to: rHuman FLt3 Active
- Gene:
- FLT3 NIH gene
- Name:
- fms related tyrosine kinase 3
- Previous symbol:
- -
- Synonyms:
- STK1, FLK2, CD135
- Chromosome:
- 13q12.2
- Locus Type:
- gene with protein product
- Date approved:
- 1990-07-30
- Date modifiied:
- 2019-04-23
Related products to: rHuman FLt3 Active
Related articles to: rHuman FLt3 Active
- Acute myeloid leukemia (AML) is an aggressive hematological malignancy with poor survival rates in adults, posing a significant economic burden. FMS-like tyrosine kinase 3 (FLT3) mutations are linked to poor prognosis in AML and resistance to clinically approved FLT3 inhibitors. Previously, we reported a novel benzimidazole-based FLT3 inhibitor, 4ACP, with nanomolar activities against FLT3-ITD and FLT3-TKD mutants, showing selective cytotoxicity against FLT3-ITD AML cell lines. In this study, we synthesized 31 derivatives by modifying the 4-acetamidophenyl group and varying substituents at N1-phenyl and C2 positions. We identified compound 21l (3-acetamidophenyl) as the most potent derivative (FLT3-TKD(D835Y) IC = 1.47 nM). Linking 21l to a solvent-accessible group yielded compound 22b, which exhibited a sub-nanomolar activity against FLT-TKD(D835Y) mutant with an IC value of 0.48 nM. Compound 22b showed preferential antiproliferative activities against MOLM-14, MV4-11, MOLM-14-D835Y, and MOLM-14-F691L AML cell lines with IC values of 16.1, 10.5, 26.5, and 160.3 nM, respectively. 22b induced dose-dependent inhibition of FLT3, ERK, STAT5, and S6 phosphorylation, G0/G1 cell-cycle arrest, and apoptotic cell death at low nanomolar concentrations in MOLM-14 and MOLM-14-D835Y cells. It was more selective for FLT3-dependent cell lines, showing about 80-fold selectivity toward FLT3-TKD(D835Y) over KIT, indicating relative safety and lower myelosuppression potential. The molecular dynamics study of 4ACP and 22b was conducted to explain the significant changes in activity resulting from subtle structural alterations. Altogether, these findings establish 22b as a potent mutant FLT3 inhibitor, warranting further investigation and optimization to target resistant AML. - Source: PubMed
El-Deen Nada AlaaDeFilippis RosaAnnaAbdel-Aziz Amal KamalMilik Sandra NPatel SuhanaIsmail Muhammad IKhaled OmarAhmed Tarek ErfanAbdelfattah Ayatullah GamalAli Eslam M HGaballah Maiy YMcPhillie Martin JAbouzid Khaled A MSerya Rabah A THenary MagedMinucci SaverioShah Neil PDokla Eman M E - Acute myeloid leukemia (AML) with KMT2A rearrangement (KMT2Ar) has poor outcomes. We analyzed 1,611 patients with AML and 4.3% demonstrated rearrangements in KMT2A. Signaling-related genes (NRAS 30%, KRAS 23% and FLT3-TKD 16%) were the most frequently mutated in patients with KMT2Ar AML. Patients treated with intensive chemotherapy (IT) achieved a complete remission (CR)/CR with incomplete blood count recovery (CRi) rate of 81%, and when combined with venetoclax, the CR/CRi rate increased to 100%. Patients treated with low intensity treatment (LIT) achieved an CR/CRi rate of 33%, and when combined with venetoclax, the CR/CRi rate was 61%. For patients treated with IT, the 5-year overall survival (OS) and event-free survival (EFS) rates were 66% and 64%, respectively, compared with 7% in those treated with LIT. Thirty-nine patients (57%) underwent allogeneic stem cell transplantation after achieving CR/CRi. For patients treated with LIT, multivariate analysis demonstrated that N/KRAS mutations were predictive for OS (HR 2.93, 95% CI 1.18-7.29, P = 0.021) and EFS (HR 3.51, 95% CI 1.35-9.24, P = 0.01). In summary, outcomes in KMT2Ar AML have improved over years in patients treated with IT, whereas those treated with LIT continue to show poor survival, highlighting the need for novel combinations. - Source: PubMed
Publication date: 2025/05/09
Bataller AlexGoulart Hannah EIssa Ghayas CDiNardo Courtney DDaver NavalKadia TapanBazinet AlexandreBouligny Ian MSenapati JayastuHaddad Fadi GBorthakur GautamSasaki KojiShort Nicholas JYilmaz MusaMontalban-Bravo GuillermoTang GuilingLoghavi SanamGarcia-Manero GuillermoRavandi FarhadKantarjian HagopJabbour Elias - Histone H3 lysine 4 trimethylation (H3K4me3) is abundant in mixed-lineage leukemia-rearranged (MLL-r) acute myeloid leukemia (AML) cells; however, the responsible enzymes and their roles remain unclear. This study aimed to identify the modifier responsible for high H3K4me3 modification in MLL-r leukemia and its downstream targets essential for the cell proliferation. Here, we performed a CRISPR-tiling screen against known H3K4 methylation modifiers in an MLL-r AML model. Disrupting the SETD1B catalytic SET domain caused depletion of FLT3-ITD or Nras-expressing AML cells, and gene expression downregulation, particularly in the MYC pathway. SETD1B SET domain loss results in a significant decrease in H3K4me3 breadth. Exogenous MYC expression or disrupting H3K4 demethylase KDM5C significantly restored growth defects in SETD1B SET domain-mutant cells. These data indicated that SETD1B was required for H3K4me3 breadth and MYC expression. Thus, a thorough understanding of SETD1B-mediated H3K4me3 breadth is critical for developing markers and therapies for MYC-dependent leukemia subtypes. - Source: PubMed
Publication date: 2025/05/08
Izumi ShintaroOhtani KoMatsumoto MakotoShibata SeitoRahmutulla BahityarFukuyo MasakiNishimoto MitsutakaMiyagawa HideoSakaida EmikoYokote KoutaroKitabayashi IssayAraki KimiKaneda AtsushiHoshii Takayuki - For patients with newly diagnosed AML not suitable for intensive induction chemotherapy, venetoclax (VEN) plus azacitidine (AZA) is a standard of care therapy. This study describes real-world (rw) treatment patterns and outcomes of patients with AML receiving initial VEN-based therapy. - Source: PubMed
Publication date: 2025/05/08
Lachowiez Curtis ABarcellos AnnaZettler Christina MBelli Andrew JFernandes Laura LHansen EricWang Ching KunOwusu Henry FZeidan Amer MStein Eytan MSwords Ronan - Risk stratification in acute myeloid leukemia (AML) is driven by genetics, yet patient age substantially influences therapeutic decisions. To evaluate how age alters the prognostic impact of genetic mutations, we pooled data from 3062 pediatric and adult AML patients from multiple cohorts. Signaling pathway mutations dominated in younger patients, while mutations in epigenetic regulators, spliceosome genes, and alterations became more frequent with increasing age. Machine learning models were trained to identify prognostic variables and predict complete remission and 2-year overall survival, achieving area-under-the-curve scores of 0.801 and 0.791, respectively. Using Shapley (SHAP) values, we quantified the contribution of each variable to model decisions and traced their impact across six age groups: infants, children, adolescents/young adults, adults, seniors, and elderly. The highest contributions to model decisions among genetic variables were found for alterations of , , inv(16), and t(8;21) conferring favorable risk and alterations of , del(5q), -7, and -17 conferring adverse risk, while -ITD had an ambiguous role conferring favorable treatment responses yet poor overall survival. Age significantly modified the prognostic value of genetic alterations, with no single alteration consistently predicting outcomes across all age groups. Specific alterations associated with aging such as , , or del(5q) posed a disproportionately higher risk in younger patients. These results challenge uniform risk stratification models and highlight the need for context-sensitive AML treatment strategies. - Source: PubMed
Publication date: 2025/05/07
Eckardt Jan-NiklasHahn WaldemarRies Rhonda EChrost Szymon DWinter SusannStasik SebastianRöllig ChristophPlatzbecker UweMüller-Tidow CarstenServe HubertBaldus Claudia DSchliemann ChristophSchäfer-Eckart KerstinHanoun MaherKaufmann MartinBurchert AndreasSchetelig JohannesBornhäuser MartinWolfien MarkusMeshinchi SoheilThiede ChristianMiddeke Jan Moritz