scholarly journals The human equilibrative nucleoside transporter 1 mediates in vitro cytarabine sensitivity in childhood acute myeloid leukaemia

2005 ◽  
Vol 93 (12) ◽  
pp. 1388-1394 ◽  
Author(s):  
I Hubeek ◽  
R W Stam ◽  
G J Peters ◽  
R Broekhuizen ◽  
J P P Meijerink ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Nucleoside Transporter ◽  
Equilibrative Nucleoside Transporter ◽  
Acute Myeloid

scholarly journals A circular RNA derived from PLXNB2 as a valuable predictor of the prognosis of patients with acute myeloid leukaemia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Leilei Lin ◽  
Yu Wang ◽  
Sicheng Bian ◽  
Lili Sun ◽  
Zhibo Guo ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Regulatory Networks ◽  
Clinical Samples ◽  
Circular Rnas ◽  
Qrt Pcr ◽  
Rna Fish ◽  
Acute Myeloid

Abstract Background As a common haematological malignancy, acute myeloid leukaemia (AML), particularly with extramedullary infiltration (EMI), often results in a high mortality rate and poor prognosis. Circular RNAs (circRNAs) regulate biological and pathogenic processes, suggesting a potential role in AML. We have previously described the overall alterations in circRNAs and their regulatory networks between patients with AML presenting with and without EMI. This study aims to find new prognostic and therapeutic targets potentially associated with AML. Methods qRT-PCR was performed on samples from 40 patients with AML and 15 healthy controls. The possibility of using circPLXNB2 (circRNA derived from PLXNB2) as a diagnostic and prognostic biomarker for AML was analysed with multiple statistical methods. In vitro, the function of circPLXNB2 was studied by lentivirus transfection, CCK-8 assays, flow cytometry, and Transwell experiments. Western blotting and qRT-PCR were performed to detect the expression of related proteins and genes. The distribution of circPLXNB2 in cells was observed using RNA fluorescence in situ hybridization (RNA-FISH). We also investigated the role of circPLXNB2 by establishing AML xenograft models in NOD/SCID mice. Results By analysing the results of qRT-PCR detection of clinical samples, the expression of the circPLXNB2 and PLXNB2 mRNAs were significantly increased in patients with AML, more specifically in patients with AML presenting with EMI. High circPLXNB2 expression was associated with an obviously shorter overall survival and leukaemia-free survival of patients with AML. The circPLXNB2 expression was positively correlated with PLXNB2 mRNA expression, as evidenced by Pearson’s correlation analysis. RNA-FISH revealed that circPLXNB2 is mainly located in the nucleus. In vitro and in vivo, circPLXNB2 promoted cell proliferation and migration and inhibited apoptosis. Notably, circPLXNB2 also increased the expression of PLXNB2, BCL2 and cyclin D1, and reduced the expression of BAX. Conclusion In summary, we validated the high expression of circPLXNB2 and PLXNB2 in patients with AML. Elevated circPLXNB2 levels were associated with poor clinical outcomes in patients with AML. Importantly, circPLXNB2 accelerated tumour growth and progression, possibly by regulating PLXNB2 expression. Our study highlights the potential of circPLXNB2 as a new prognostic predictor and therapeutic target for AML in the future.

scholarly journals Pre-clinical activity of combined LSD1 and mTORC1 inhibition in MLL-translocated acute myeloid leukaemia

Leukemia ◽  
2019 ◽  
Vol 34 (5) ◽  
pp. 1266-1277 ◽  
Author(s):  
Gauri Deb ◽  
Bettina Wingelhofer ◽  
Fabio M. R. Amaral ◽  
Alba Maiques-Diaz ◽  
John A. Chadwick ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Residual Disease ◽  
Molecular Subtype ◽  
Clinical Activity ◽  
Lineage Differentiation ◽  
A Genome ◽  
Acute Myeloid

AbstractThe histone demethylase lysine-specific demethylase 1 (LSD1 or KDM1A) has emerged as a candidate therapeutic target in acute myeloid leukaemia (AML); tranylcypromine-derivative inhibitors induce loss of clonogenic activity and promote differentiation, in particular in the MLL-translocated molecular subtype of AML. In AML, the use of drugs in combination often delivers superior clinical activity. To identify genes and cellular pathways that collaborate with LSD1 to maintain the leukaemic phenotype, and which could be targeted by combination therapies, we performed a genome-wide CRISPR-Cas9 dropout screen. We identified multiple components of the amino acid sensing arm of mTORC1 signalling—RRAGA, MLST8, WDR24 and LAMTOR2—as cellular sensitizers to LSD1 inhibition. Knockdown of mTORC1 components, or mTORC1 pharmacologic inhibition, in combination with LSD1 inhibition enhanced differentiation in both cell line and primary cell settings, in vitro and in vivo, and substantially reduced the frequency of clonogenic primary human AML cells in a modelled minimal residual disease setting. Synergistic upregulation of a set of transcription factor genes associated with terminal monocytic lineage differentiation was observed. Thus, dual mTORC1 and LSD1 inhibition represents a candidate combination approach for enhanced differentiation in MLL-translocated AML which could be evaluated in early phase clinical trials.

L-Gossypol Has Significant In Vitro Activity Against Primary Acute Myeloid Leukaemia Cells, Inducing Apoptosis through the Intrinsic Pathway.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4180-4180
Author(s):  
Hani Y. Osman ◽  
Steven Knapper ◽  
Alan K. Burnett
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
White Cell Count ◽  
Annexin V ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Intrinsic Pathway ◽  
Clinical Role ◽  
Acute Myeloid

Abstract The potential anti-tumor effect of the polyphenolic cotton oilseed extract gossypol has been known for a number of years. Studies in cell lines and primary tumor material have suggested both antiproliferative effects and the induction of apoptosis (Huang et al. Anticancer research 26:3a) with activity being seen against even multidrug resistant tumors. Although the mechanism of action of gossypol has not yet been well-characterised, there is some evidence that it may block the binding of the apoptotic regulator BCL-2 with the pro-apoptotic proteins BAX and BAD (Prada et al. blood 106:11). Acute myeloid leukaemia (AML) is characterised by accumulation of primitive blasts in bone marrow and peripheral blood. The disease is highly heterogeneous and inherently resistant to therapy, dysregulation of apoptosis frequently leading to a survival advantage in blast cells. We studied the in vitro activity of gossypol against cryopreserved primary blasts obtained from 44 AML patients. Cells were incubated for 48 hours with a range of concentrations of gossypol, this being followed by MTS cytotoxicity assay. IC50 concentrations ranged from 792nM to in excess of 100 mM (median 22.791 mM). Statistical analysis showed no significant variation in drug sensitivity according to sex, age, presenting white cell count, FLT3 mutation status, karyotype or clinical outcome measures. The in vitro combination of gossypol with the cytotoxic agent cytosine arabinoside (AraC) was assessed in 40 primary samples using the median effects principle of Chou and Talalay. The median combination index of 0.946 suggested an overall additive effect when the agents were combined, although numbers were insufficient to establish this conclusively (95% CI for median 0.84–1.31). Flow cytometric annexin V binding assay confirmed apoptosis to be the principal mode of cell death in response to gossypol, cell viability obtained using this method correlating well with that obtained using the MTS assay. Gossypol caused downstream activation of Caspase 3/7 via Caspase 9 as determined by luminometric analysis, indicating that the intrinsic pathway is the main inducer of this cycle. Gossypol is effective in inducing apoptosis in primary AML blasts and there is potential for greater efficacy when used in combination with cytotoxic chemotherapy. Further in vitro development of this agent is now required to further define its future clinical role.

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