scholarly journals A Novel Fusion Between MOZ and the Nuclear Receptor Coactivator TIF2 in Acute Myeloid Leukemia

Blood ◽  
1998 ◽  
Vol 91 (9) ◽  
pp. 3127-3133 ◽  
Author(s):  
Melina Carapeti ◽  
Ricardo C.T. Aguiar ◽  
John M. Goldman ◽  
Nicholas C.P. Cross
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nuclear Receptor ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Chromosomal Abnormalities ◽  
Leukemia Cell ◽  
Cell Phenotype ◽  
Nuclear Receptor Coactivator ◽  
Blast Cells ◽  
Acute Myeloid

Chromosomal abnormalities of band 8p11 are associated with a distinct subtype of acute myeloid leukemia with French-American-British M4/5 morphology and prominent erythrophagocytosis by the blast cells. This subtype is usually associated with the t(8;16)(p11;p13), a translocation that has recently been shown to result in a fusion between the MOZ and CBP genes. We have cloned the inv(8)(p11q13), an abnormality associated with the same leukemia phenotype, and found a novel fusion between MOZ and the nuclear receptor transcriptional coactivatorTIF2/GRIP-1/NCoA-2. This gene has not previously been implicated in the pathogenesis of leukemia or other malignancies. MOZ-TIF2 retains the histone acetyltransferase homology domains of both proteins and also the CBP binding domain of TIF2. We speculate that the apparently identical leukemia cell phenotype observed in cases with the t(8;16) and the inv(8) arises by recruitment of CBP by MOZ-TIF2, resulting in modulation of the transcriptional activity of target genes by a mechanism involving abnormal histone acetylation.

scholarly journals A Novel Fusion Between MOZ and the Nuclear Receptor Coactivator TIF2 in Acute Myeloid Leukemia

Blood ◽  
1998 ◽  
Vol 91 (9) ◽  
pp. 3127-3133 ◽  
Author(s):  
Melina Carapeti ◽  
Ricardo C.T. Aguiar ◽  
John M. Goldman ◽  
Nicholas C.P. Cross
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nuclear Receptor ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Chromosomal Abnormalities ◽  
Leukemia Cell ◽  
Cell Phenotype ◽  
Nuclear Receptor Coactivator ◽  
Blast Cells ◽  
Acute Myeloid

Abstract Chromosomal abnormalities of band 8p11 are associated with a distinct subtype of acute myeloid leukemia with French-American-British M4/5 morphology and prominent erythrophagocytosis by the blast cells. This subtype is usually associated with the t(8;16)(p11;p13), a translocation that has recently been shown to result in a fusion between the MOZ and CBP genes. We have cloned the inv(8)(p11q13), an abnormality associated with the same leukemia phenotype, and found a novel fusion between MOZ and the nuclear receptor transcriptional coactivatorTIF2/GRIP-1/NCoA-2. This gene has not previously been implicated in the pathogenesis of leukemia or other malignancies. MOZ-TIF2 retains the histone acetyltransferase homology domains of both proteins and also the CBP binding domain of TIF2. We speculate that the apparently identical leukemia cell phenotype observed in cases with the t(8;16) and the inv(8) arises by recruitment of CBP by MOZ-TIF2, resulting in modulation of the transcriptional activity of target genes by a mechanism involving abnormal histone acetylation.

Hypomethylation of Tumor Suppressor Genes in Acute Myeloid Leukemia: Characteristic of Cell Lines with MLL Abnormalities?.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 365-365
Author(s):  
Hilmar Quentmeier ◽  
Sonja Röhrs ◽  
Wilhelm G Dirks ◽  
Claus Meyer ◽  
Rolf Marschalek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tumor Suppressor ◽  
Acute Leukemia ◽  
Cell Lines ◽  
Fusion Proteins ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Leukemia Cell ◽  
Hoxa Cluster ◽  
Acute Myeloid

Abstract Abstract 365 Background: Translocations of the Mixed Lineage Leukemia (MLL) gene occur in a subset (5%) of acute myeloid leukemia (AML) and in mixed phenotype acute leukemia in infancy, a disease with extremely poor prognosis. Animal model systems show that MLL gain of function mutations may contribute to leukemogenesis. Wild-type MLL carries histone methyltransferase activity and affects specific target genes, such us HOXA cluster genes. While the more than three dozen MLL fusion proteins known today exert different specific functions, they finally induce transcription of individual target genes. Consequently, acute lymphoblastic leukemias (ALL) with MLL mutations (MLLmu) exhibit typical gene expression profiles including high-level expression of HOXA cluster genes. Aim of this study was to find a correlation between the MLL mutational status and tumor suppressor gene methylation/expression in acute leukemia cell lines. Results: Using MS-MLPA (methylation-specific multiplex ligation-dependent probe amplification assay), methylation of 24 different TSG was analyzed in 28 MLLmu and MLLwt acute leukemia cell lines. 1.8/24 TSG were methylated in MLLmu AML cells, 6.2/24 TSG were methylated in MLLwt AML cells. Hypomethylation and expression of the tumor suppressor genes (TSG) BEX2, IGSF4 and TIMP3 turned out to be characteristic of MLLmu acute myeloid leukemia (AML) cell lines. MLL wild-type (MLLwt) AML cell lines displayed hypermethylated TSG promoters resulting in transcriptional silencing. Demethylating agents and inhibitors of histone deacetylases restored expression of BEX2, IGSF4 and TIMP3 confirming epigenetic silencing of these genes in MLLwt cells. The positive correlation between MLL translocation, TSG hypomethylation and expression suggested that MLL fusion proteins were responsible for dysregulation of TSG expression in MLLmu cells. This concept was supported by our observation that Bex2 mRNA levels in MLL-ENL transgenic mouse cell lines required expression of the MLL fusion gene. Conclusion: These results suggest that the conspicuous expression of the TSG BEX2, IGSF4 and TIMP3 in MLLmu AML cell lines is the consequence of altered epigenetic properties of MLL fusion proteins. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Therapeutic inhibition of GAS6-AS1/YBX1/MYC axis suppresses cell propagation and disease progression of acute myeloid leukemia

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Hao Zhou ◽  
Wei Liu ◽  
Yongming Zhou ◽  
Zhenya Hong ◽  
Jian Ni ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Leukemia Cell ◽  
Treatment Strategies ◽  
Network Analyses ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Its therapy has not significantly improved during the past four decades despite intense research efforts. New molecularly targeted therapies are in great need. The proto-oncogene c-Myc (MYC) is an attractive target due to its transactivation role in multiple signaling cascades. Deregulation of the MYC is considered one of a series of oncogenic events required for tumorigenesis. However, limited knowledge is available on which mechanism underlie MYC dysregulation and how long non-coding RNAs (lncRNAs) are involved in MYC dysregulation in AML. Methods AML microarray chips and public datasets were screened to identify novel lncRNA GAS6-AS1 was dysregulated in AML. Gain or loss of functional leukemia cell models were produced, and in vitro and in vivo experiments were applied to demonstrate its leukemogenic phenotypes. Interactive network analyses were performed to define intrinsic mechanism. Results We identified GAS6-AS1 was overexpressed in AML, and its aberrant function lead to more aggressive leukemia phenotypes and poorer survival outcomes. We revealed that GAS6-AS1 directly binds Y-box binding protein 1 (YBX1) to facilitate its interaction with MYC, leading to MYC transactivation and upregulation of IL1R1, RAB27B and other MYC target genes associated with leukemia progression. Further, lentiviral-based GAS6-AS1 silencing inhibited leukemia progression in vivo. Conclusions Our findings revealed a previously unappreciated role of GAS6-AS1 as an oncogenic lncRNA in AML progression and prognostic prediction. Importantly, we demonstrated that therapeutic targeting of the GAS6-AS1/YBX1/MYC axis inhibits AML cellular propagation and disease progression. Our insight in lncRNA associated MYC-driven leukemogenesis may contribute to develop new anti-leukemia treatment strategies.

scholarly journals Activation of C/EBPa Myeloid-Specific Transcription Factor By NAMPT/SIRT1-Triggered Deacetylation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2199-2199
Author(s):  
Bardia Samareh ◽  
Masoud Nasri ◽  
Inna Zimmer ◽  
Olga Klimenkova ◽  
Leonie Keller ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Leukemia Cell ◽  
Myeloid Differentiation ◽  
Granulocytic Differentiation ◽  
Acute Myeloid ◽  
Myeloid Leukemia Cell

Abstract Previously, we described new mechanism of G-CSF-triggered granulocytic differentiation of hematopoietic stem cells (HSCs) via activation of the enzyme Nicotinamide Phosphorybosyltransferase (NAMPT) leading to NAD+ production and activation of NAD+ -dependent protein deacetylase sirtuin 1 (SIRT1). We found, that upon stimulation of HSCs with NAMPT, SIRT1 bound to the key myeloid transcription factor C/EBPα followed by transcriptional induction of C/EBPα target genes G-CSFR and G-CSF and granulocytic differentiation. In the present work we investigated the mechanism of NAMPT/SIRT1-triggered deacetylation of C/EBPα. We found that C/EBPα is acetylated at the position Lys 161, which is evolutionarily conserved. Lys 161 is localized in the transactivation element III (TE-III) of the transactivation domain (TAD) of C/EBPα protein, which is responsible for recruitment of SWI/SNF and CDK2/CDK4. Western blot and DUOLINK analysis using rabbit polyclonal antibody specifically recognizing acetyl-Lys 161 of C/EBPα revealed predominantly nuclear localization of acetylated C/EBPα protein in acute myeloid leukemia cell lines NB4 and HL60 as well as in primary HSCs. Induction of myeloid differentiation of HSCs by treatment with G-CSF as well as ATRA-induced differentiation of NB4 cells resulted in the deacetylation of C/EBPα. NAMPT inhibition in NB4 and HL60 cell lines using specific inhibitor FK866 led to the dramatically elevated levels of acetylated C/EBPα and reduced amounts of total C/EBPα protein, which was in line with diminished mRNA expression of C/EBPα target genes (G-CSF, G-CSFR and ELANE). Interestingly, treatment of acute myeloid leukemia cell line HL60 with NAMPT or transduction of HL-60 cells with NAMPT-expressing lentiviral construct induced myeloid differentiation of these cells even without addition of ATRA. This was in line with time- and dose-dependent increase of total C/EBPα protein levels upon NAMPT treatment. Therefore, NAMPT overcomes transcriptional repression of C/EBPα in HL-60 cells by activation of positive CEBPA autoregulation. Taken together, we described a new mechanism of regulation of C/EBPα activities in hematopoiesis and leukemogenesis by its post-translational modification via NAMPT/SIRT1-triggered de-/acetylation. Disclosures No relevant conflicts of interest to declare.

Drug-sensitivity of resistant acute myeloid leukemia cell line to Doxorubicin is enhanced by Triptolide through down-regulation of HIF-1α and Nrf2

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4921-4921
Author(s):  
Bing Xu ◽  
Feili Chen ◽  
Yuejian Liu ◽  
Shiyun Wang ◽  
Rongwei Li ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Line ◽  
Myeloid Leukemia ◽  
Drug Sensitivity ◽  
Target Genes ◽  
Leukemia Cell ◽  
Acute Myeloid Leukemia Cell ◽  
Leukemia Cell Line ◽  
Acute Myeloid ◽  
Myeloid Leukemia Cell

Abstract Background Relapse and treatment-related complication have been the hurdle for the cure of acute myeloid leukemia patients. Finding a new drug-sensitizer could significantly prolong the survival time of patients. Triptolide (TPL) has been shown to enhance the drug-sensitivity of a variety of cancer cells when used in a low-concentration. HL60/DOX is a kind of acute myeloid leukemia cell line which is resistant to a commonly used drug Doxorubicin. This kind of cell line is widely used in the study of drug-sensitization. Aim This study aims to investigate whether low-dose TPL could enhance the drug-sensitivity of resistant acute myeloid leukemia cell line HL60/DOX to Doxorubicin and related mechanism. Method HL60/DOX cells were subjected to different treatments and thereafter MTT assay, flow cytometry and Western blot or RT-PCR were used to determine IC50, apoptotic status and expression of Nrf2, HIF-1α and their target genes. Results HL60/DOX cells were exposed to increasing concentrations of Doxorubicin with TPL at a constant IC20 concentration (14nM) for 48h. In comparison with anticancer agent alone, TPL enhanced the cytotoxicity of Doxorubicin (IC50:14.36±2.23 vs. 7.9±0.33μM, 1.82 fold; P=0.008) to HL60/DOX. Results of combination index showed that TPL and anti-cancer agents had synergistic effects when fraction affected was below 60%. Flow cytometry analysis also showed that apoptoticratio of cells treated by Doxorubicin together with TPL was significantly increased compared to cell streated by Doxorubicin alone (19.55±1.70%vs. 72.62±4.83%, P<0.01). Next, we explored the underlying mechanism. Hypoxia-inducible factor- 1α (HIF-1α) is the major mediator of hypoxic responses in malignant cells. High expression of it is correlated with bad clinical outcome in patients. It is also important for the survival of leukemia stem cells which are responsible for relapse. Nrf2 is an important protective factor which is correlated with chemo-resistance in cancer cells. When combined with TPL, Doxorubicin down-regulates Nrf2 and HIF-1α expression at protein and mRNA levels. Down-stream genes of Nrf2 e.g NQO1, GSR and HO-1 as well as target genes of HIF-1α e.g BNIP3, VEGF and CAIX are also down-regulated at mRNA level. Conclusion Inconclusion, our study demonstrates that TPL could enhance drug-sensitivity of HL60/DOX in vitro through down-regulation of Nrf2 and HIF-1α, providing the experimental base for further study. Disclosures: No relevant conflicts of interest to declare.

scholarly journals RELATIONSHIP OF BLAST CELL IMMUNOPHENOTYPE WITH REMISSION IN ACUTE MYELOID LEUKEMIA IN CHILDREN

2020 ◽  
Vol 19 (4) ◽  
pp. 45-53
Author(s):  
A. D. Palladina ◽  
A. V. Popa ◽  
V. G. Nikitaev ◽  
K. L. Kondratchik ◽  
N. A. Kupryshina ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tumor Cells ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Remission Rate ◽  
Specific Gene ◽  
Blood Leukocytes ◽  
Blast Cells ◽  
The Relationship ◽  
Acute Myeloid

Introduction. Acute myeloid leukemia (AML) is a clonal disease of the blood system that occurs as a result of mutations in the genome of hematopoietic progenitor cells. As a result of mutations, the linear differentiation of hematopoietic cells is replaced by the proliferation of malignant myeloid progenitors. Currently, the risk group for AML in children is determined mainly by the presence of specific gene and chromosomal abnormalities and an increased level of peripheral blood leukocytes. The features of the immunophenotype of blast cells can also influence the course of the disease.The aim of the work is to assess the relationship between the immunophenotypic parameters of blast cells and the probability of achieving remission in children with AML.Materials and methods. The study included 109 patients aged 3 months to 17 years who received treatment according to the AML BFM 87, AML BFM 2004, NII DOG AML 2007 и NII DOG AML 2012 protocol in the period from 1991 to 2020.Results. The study showed the relationship between the probability of achieving remission and the presence of markers CD33, CD19 and CD14 on tumor cells. Expression of lymphoid antigen CD19 on blasts was associated with a higher rate of remission (73.0 % vs 95.5 %, p = 0.027). The absence of the linearly associated myeloid marker CD33 negatively correlated with the remission rate (61.1 % vs 87.7 %, p = 0.007). In the presence of monocyte antigen CD14 on blasts, the probability of achieving remission was low (95 % vs 50 %, p = 0.013).Conclusion. Characteristics of the immunophenotype of tumor cells in AML in children are associated with the probability of achieving remission.

scholarly journals A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Matthew E. Massett ◽  
Laura Monaghan ◽  
Shaun Patterson ◽  
Niamh Mannion ◽  
Roderick P. Bunschoten ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cell Activity ◽  
Leukemia Cell ◽  
Gene Signature ◽  
Pathological Feature ◽  
Self Renewal ◽  
Stem Cell Activity ◽  
Molecular Mechanism Of Action ◽  
Acute Myeloid

AbstractEpigenomic dysregulation is a common pathological feature in human hematological malignancies. H3K9me3 emerges as an important epigenomic marker in acute myeloid leukemia (AML). Its associated methyltransferases, such as SETDB1, suppress AML leukemogenesis, whilst H3K9me3 demethylases KDM4C is required for mixed-lineage leukemia rearranged AML. However, the specific role and molecular mechanism of action of another member of the KDM4 family, KDM4A has not previously been clearly defined. In this study, we delineated and functionally validated the epigenomic network regulated by KDM4A. We show that selective loss of KDM4A is sufficient to induce apoptosis in a broad spectrum of human AML cells. This detrimental phenotype results from a global accumulation of H3K9me3 and H3K27me3 at KDM4A targeted genomic loci thereby causing downregulation of a KDM4A-PAF1 controlled transcriptional program essential for leukemogenesis, distinct from that of KDM4C. From this regulatory network, we further extracted a KDM4A-9 gene signature enriched with leukemia stem cell activity; the KDM4A-9 score alone or in combination with the known LSC17 score, effectively stratifies high-risk AML patients. Together, these results establish the essential and unique role of KDM4A for AML self-renewal and survival, supporting further investigation of KDM4A and its targets as a potential therapeutic vulnerability in AML.

Sign in / Sign up

Export Citation Format

Share Document