scholarly journals Genome-wide characterization of lncRNAs in acute myeloid leukemia

2017 ◽  
Vol 19 (4) ◽  
pp. 627-635 ◽  
Author(s):  
Lijun Lei ◽  
Siyu Xia ◽  
Dan Liu ◽  
Xiaoqing Li ◽  
Jing Feng ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Expression Patterns ◽  
Critical Role ◽  
Noncoding Rnas ◽  
Large Family ◽  
Genome Wide ◽  
Key Factor ◽  
Acute Myeloid ◽  
Control Samples

Abstract Long noncoding RNAs (lncRNAs) are a large family of noncoding RNAs that play a critical role in various normal bioprocesses as well as tumorigenesis. However, the expression patterns and biological functions of lncRNAs in acute leukemia have not been well studied. Here, we performed transcriptome-wide lncRNA expression profiling of acute myeloid leukemia (AML) patient samples, along with non-leukemia control hematopoietic samples. We found that lncRNAs were differentially expressed in AML samples relative to control samples. Notably, we identified that lncRNAs upregulated in AML (relative to the control samples) are associated with a lower degree of DNA methylation and a higher ratio of being bound by transcription factors such as SP1, STAT4, ATF-2 and ELK-1 compared with those downregulated in AML. Moreover, an enrichment of H3K4me3 and a depletion of H3K27me3 were observed in upregulated lncRNAs in AML. Expression patterns of three types of lncRNAs (antisense, enhancer and intergenic lncRNAs) have previously been characterized. Of the identified lncRNAs, we found that high expression level lncRNA LOC285758 is associated with the poor prognosis in AML patients. Furthermore, we found that LOC285758 regulates proliferation of AML cell lines by enhancing the expression of HDAC2, a key factor in carcinogenesis. Collectively, our study depicts a landscape of important lncRNAs in AML and provides novel potential therapeutic targets and prognostic markers for AML treatment.

scholarly journals Critical Role of c-Myc in Acute Myeloid Leukemia Involving Direct Regulation of miR-26a and Histone Methyltransferase EZH2

2011 ◽  
Vol 2 (5) ◽  
pp. 585-592 ◽  
Author(s):  
B. Salvatori ◽  
I. Iosue ◽  
N. Djodji Damas ◽  
A. Mangiavacchi ◽  
S. Chiaretti ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Histone Methyltransferase ◽  
Direct Regulation ◽  
Acute Myeloid

Long noncoding RNAs: A novel insight in the leukemogenesis and drug resistance in acute myeloid leukemia

2021 ◽  
Author(s):  
Anuradha Kirtonia ◽  
Milad Ashrafizadeh ◽  
Ali Zarrabi ◽  
Kiavash Hushmandi ◽  
Amirhossein Zabolian ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Acute Myeloid

microRNAs in acute myeloid leukemia: Expression patterns, correlations with genetic and clinical parameters, and prognostic significance

2009 ◽  
pp. n/a-n/a ◽  
Author(s):  
Rotraud Wieser ◽  
Marcel Scheideler ◽  
Hubert Hackl ◽  
Maria Engelmann ◽  
Christine Schneckenleithner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Expression Patterns ◽  
Prognostic Significance ◽  
Clinical Parameters ◽  
Acute Myeloid

scholarly journals A Genome-Wide Aberrant RNA Splicing in Patients with Acute Myeloid Leukemia Identifies Novel Potential Disease Markers and Therapeutic Targets

2013 ◽  
Vol 20 (5) ◽  
pp. 1135-1145 ◽  
Author(s):  
Sophia Adamia ◽  
Benjamin Haibe-Kains ◽  
Patrick M. Pilarski ◽  
Michal Bar-Natan ◽  
Samuel Pevzner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Rna Splicing ◽  
Myeloid Leukemia ◽  
Therapeutic Targets ◽  
Disease Markers ◽  
Genome Wide ◽  
A Genome ◽  
Aberrant Rna ◽  
Acute Myeloid

scholarly journals Genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways mediating sorafenib resistance in acute myeloid leukemia

Haematologica ◽  
2020 ◽  
Author(s):  
Alisa Damnernsawad ◽  
Daniel Bottomly ◽  
Stephen E. Kurtz ◽  
Christopher A. Eide ◽  
Shannon K. McWeeney ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Mek Inhibitors ◽  
Genome Wide ◽  
A Genome ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Crispr Screen ◽  
Acute Myeloid

Drug resistance impedes the long-term effect of targeted therapies in acute myeloid leukemia (AML), necessitating the identification of mechanisms underlying resistance. Approximately 25% of AML patients carry FLT3 mutations and develop post-treatment insensitivity to FLT3 inhibitors, including sorafenib. Using a genome-wide CRISPR screen, we identified LZTR1, NF1, TSC1 or TSC2, negative regulators of the MAPK and MTOR pathways, as mediators of sorafenib resistance. Analyses of ex vivo drug sensitivity assays in FLT3-ITD AML patient samples revealed lower expression of LZTR1, NF1, and TSC2 correlated with sorafenib sensitivity. Importantly, MAPK and/or MTOR complex1 (MTORC1) activity were upregulated in AML cells made resistant to several FLT3 inhibitors, including crenolanib, quizartinib, or sorafenib. These cells were sensitive to MEK inhibitors, and the combination of FLT3 and MEK inhibitors showed enhanced efficacy, suggesting its effectiveness in AML patients with FLT3 mutations and those with resistance to FLT3 inhibitors.

scholarly journals Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for Acute Myeloid Leukemia

Oncotarget ◽  
2016 ◽  
Vol 8 (5) ◽  
pp. 7891-7899 ◽  
Author(s):  
Hongchao Lv ◽  
Mingming Zhang ◽  
Zhenwei Shang ◽  
Jin Li ◽  
Shanshan Zhang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Association Study ◽  
Myeloid Leukemia ◽  
Haplotype Association ◽  
Risk Gene ◽  
Genome Wide ◽  
Fgfr2 Gene ◽  
Acute Myeloid

scholarly journals Pan-RAF Inhibition Shows Anti-Leukemic Activity in RAS-Mutant Acute Myeloid Leukemia Cells and Potentiates the Effect of Sorafenib in Cells with FLT3 Mutation

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3511
Author(s):  
Joseph D. Khoury ◽  
Mehrnoosh Tashakori ◽  
Hong Yang ◽  
Sanam Loghavi ◽  
Ying Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Signaling ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Cyclin B1 ◽  
Leukemic Cells ◽  
Phase Array ◽  
Flt3 Mutations ◽  
The Impact ◽  
Acute Myeloid

RAF molecules play a critical role in cell signaling through their integral impact on the RAS/RAF/MEK/ERK signaling pathway, which is constitutively activated in a sizeable subset of acute myeloid leukemia (AML) patients. We evaluated the impact of pan-RAF inhibition using LY3009120 in AML cells harboring mutations upstream and downstream of RAF. LY3009120 had anti-proliferative and pro-apoptotic effects and suppressed pERK1/2 levels in leukemic cells with RAS and FLT3 mutations. Using reverse protein phase array analysis, we identified reductions in the expression/activation of cell signaling components downstream of RAF (activated p38) and cell cycle regulators (Wee1/cyclin B1, Cdc2/Cdk1, activated Rb, etc.). Notably, LY3009120 potentiated the effect of Ara-C on AML cells and overcame bone marrow mesenchymal stromal cell-mediated chemoresistance, with RAS-mutated cells showing a notable reduction in pAKT (Ser473). Furthermore, the combination of LY3009120 and sorafenib resulted in significantly higher levels of apoptosis in AML cells with heterozygous and hemizygous FLT3 mutations. In conclusion, pan-RAF inhibition in AML using LY3009120 results in anti-leukemic activity, and combination with Ara-C or sorafenib potentiates its effect.

scholarly journals SETDB1 mediated histone H3 lysine 9 methylation suppresses MLL-fusion target expression and leukemic transformation

Haematologica ◽  
2019 ◽  
Vol 105 (9) ◽  
pp. 2273-2285 ◽  
Author(s):  
James Ropa ◽  
Nirmalya Saha ◽  
Hsiangyu Hu ◽  
Luke F. Peterson ◽  
Moshe Talpaz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Critical Role ◽  
High Expression ◽  
Leukemia Cells ◽  
Biological Impact ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Epigenetic regulators play a critical role in normal and malignant hematopoiesis. Deregulation, including epigenetic deregulation, of the HOXA gene cluster drives transformation of about 50% of acute myeloid leukemia. We recently showed that the Histone 3 Lysine 9 methyltransferase SETDB1 negatively regulates the expression of the pro-leukemic genes Hoxa9 and its cofactor Meis1 through deposition of promoter H3K9 trimethylation in MLL-AF9 leukemia cells. Here, we investigated the biological impact of altered SETDB1 expression and changes in H3K9 methylation on acute myeloid leukemia. We demonstrate that SETDB1 expression is correlated to disease status and overall survival in acute myeloid leukemia patients. We recapitulated these findings in mice, where high expression of SETDB1 delayed MLL-AF9 mediated disease progression by promoting differentiation of leukemia cells. We also explored the biological impact of treating normal and malignant hematopoietic cells with an H3K9 methyltransferase inhibitor, UNC0638. While myeloid leukemia cells demonstrate cytotoxicity to UNC0638 treatment, normal bone marrow cells exhibit an expansion of cKit+ hematopoietic stem and progenitor cells. Consistent with these data, we show that bone marrow treated with UNC0638 is more amenable to transformation by MLL-AF9. Next generation sequencing of leukemia cells shows that high expression of SETDB1 induces repressive changes to the promoter epigenome and downregulation of genes linked with acute myeloid leukemia, including Dock1 and the MLL-AF9 target genes Hoxa9, Six1, and others. These data reveal novel targets of SETDB1 in leukemia that point to a role for SETDB1 in negatively regulating pro-leukemic target genes and suppressing acute myeloid leukemia.

Abstract 4763: Genome-wide CRISPR screening identifies TSC1 as a regulator of sorafenib resistance in acute myeloid leukemia

2019 ◽  
Author(s):  
Alisa Damnernsawad ◽  
Tamilla Nechiporuk ◽  
Steve E. Kurtz ◽  
Wesley R. Horton ◽  
Olga Nikolova ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Genome Wide ◽  
Acute Myeloid

Abstract 4763: Genome-wide CRISPR screening identifies TSC1 as a regulator of sorafenib resistance in acute myeloid leukemia

2019 ◽  
Author(s):  
Alisa Damnernsawad ◽  
Tamilla Nechiporuk ◽  
Steve E. Kurtz ◽  
Wesley R. Horton ◽  
Olga Nikolova ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Genome Wide ◽  
Acute Myeloid
Sign in / Sign up

Export Citation Format

Share Document