scholarly journals Transcription Factor MEF2D is Required for the Maintenance of MLL-rearranged Acute Myeloid Leukemia

2021 ◽  
Author(s):  
Lianzhong Zhao ◽  
Pengcheng Zhang ◽  
Phillip M Galbo ◽  
Xinyue Zhou ◽  
Sajesan Aryal ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Leukemia Cell ◽  
Myeloid Differentiation ◽  
Growth Defect ◽  
Strong Negative Correlation ◽  
Acute Myeloid

Acute myeloid leukemia (AML) with MLL-rearrangement (MLL-r) comprises approximately 10% of all AML cases and portends poor outcomes. Much remains uncovered on how MLL-r AML drives leukemia development while preventing cells from normal myeloid differentiation. Here, we identified that transcription factor MEF2D is a super-enhancer-associated, highly expressed gene in MLL-r AML. Knockout of MEF2D profoundly impaired leukemia growth, induced myeloid differentiation, and delayed oncogenic progression in vivo. Mechanistically, MEF2D loss led to robust activation of a CEBPE-centered myeloid differentiation program in AML cells. Chromatin profiling revealed that MEF2D binds to and suppresses the chromatin accessibility of CEBPE cis-regulatory regions. In human acute leukemia samples, MEF2D expression showed a strong negative correlation with the expression of CEBPE. Depletion of CEBPE partially rescued the cell growth defect and myeloid cell differentiation induced by the loss of MEF2D. Lastly, we show that MEF2D is positively regulated by HOXA9, and downregulation of MEF2D is an important mechanism for DOT1L inhibitor-induced anti-leukemia effects. Collectively, our findings suggest that MEF2D plays a critical role in human MLL-r AML and uncover the MEF2D-CEBPE axis as a crucial transcriptional mechanism regulating leukemia cell self-renewal and differentiation block.

scholarly journals The Transcription Factor PU.1 Controls a Reversible Differentiation Program in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3930-3930
Author(s):  
Mark D McKenzie ◽  
Margherita Ghisi ◽  
Luisa Cimmino ◽  
Michael Erlichster ◽  
Ethan P Oxley ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Significant Loss ◽  
Polymorphonuclear Neutrophil ◽  
Myeloid Differentiation ◽  
Myeloid Lineage ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is an aggressive malignancy characterized by clonal expansion of transformed myeloid precursors that fail to differentiate into mature cells. Since myeloid lineage maturation curbs self-renewal and is considered irreversible, engaging this process in AML is an attractive therapeutic strategy. Results: Normal myeloid differentiation requires the transcription factor PU.1 (SPI1), which is functionally compromised in several AML subtypes and is directly inhibited by the recurrent fusion oncoproteins AML1-ETO and PML-RARA. To examine the importance of PU.1 suppression in AML maintenance in vivo, we have combined RNAi-mediated PU.1 inhibition with p53 deficiency to drive highly aggressive AML in mice. Using these models we find that restoring endogenous PU.1 activity in established AML in vivo is sufficient to trigger robust transcriptional, immunophenotypic, and morphological differentiation of leukemic blasts, yielding polymorphonuclear, neutrophil-like cells. Maturation of AML is associated with significant loss of cell viability and yields sustained disease clearance in vivo. Although PU.1 restoration is potently anti-leukemic, remarkably we find that subsequent suppression of PU.1 in mature neutrophil-like cells reverts them to a transformed state within several days. While mature AML-derived cells are slower to form blast colonies in methylcellulose cultures, their clonogenic frequency is only reduced four-fold relative to AML blasts suggesting highly efficient de-differentiation. Conclusions: These results demonstrate that triggering myeloid differentiation can effectively resolve a p53-deficient model of treatment resistant AML, but also identify a previously unrecognised ability of AML cells to bidirectionally transition between transformed and differentiated states based on the activity of a single transcription factor. Our findings challenge the concept of 'terminal differentiation' in AML and highlight the importance of therapeutically eradicating leukemia cells at all stages of myeloid lineage maturation. Disclosures No relevant conflicts of interest to declare.

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.

scholarly journals Anti-leukemia properties of cadmium nanoparticles in the in vitro and in vivo condition: A chemobiological study

2021 ◽  
Author(s):  
Yudi Miao ◽  
Behnam Mahdavi ◽  
Mohammad Zangeneh
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Aqueous Extract ◽  
Myeloid Leukemia ◽  
Antioxidant Properties ◽  
Leukemia Cell ◽  
Sem Images ◽  
Acute Myeloid

IntroductionThe present study investigated the anti-acute myeloid leukemia effects of Ziziphora clinopodides Lam leaf aqueous extract conjugated cadmium nanoparticles.Material and methodsTo synthesize CdNPs, Z. clinopodides aqueous extract was mixed with Cd(NO3)2 .4H2O. The characterization of the biosynthesized cadmium nanoparticles was carried out using many various techniques such as UV-Vis. and FT-IR spectroscopy, XRD, FE-SEM, and EDS.ResultsThe uniform spherical morphology of NPs was proved by FE-SEM images with NPs the average size of 26.78cnm. For investigating the antioxidant properties of Cd(NO3)2, Z. clinopodides, CdNPs, and Daunorubicin, the DPPH test was used. The cadmium nanoparticles inhibited half of the DPPH molecules in a concentration of 196 µg/mL. To survey the cytotoxicity and anti-acute myeloid leukemia effects of Cd(NO3)2, Z. clinopodides, CdNPs, and Daunorubicin, MTT assay was used on the human acute myeloid leukemia cell lines i.e., Murine C1498, 32D-FLT3-ITD, and Human HL-60/vcr. The IC50 of the cadmium nanoparticles was 168, 205, and 210 µg/mL against Murine C1498, 32D-FLT3-ITD, and Human HL-60/vcr cell lines, respectively. In the part of in vivo study, DMBA was used for inducing acute myeloid leukemia in mice. CdNPs similar to daunorubicin ameliorated significantly (p≤0.01) the biochemical, inflammatory, RBC, WBC, platelet, stereological, histopathological, and cellular-molecular parameters compared to the other groups.ConclusionsAs mentioned, the cadmium nanoparticles had significant anti-acute myeloid leukemia effects. After approving the above results in the clinical trial studies, these cadmium nanoparticles can be used as a chemotherapeutic drug to treat acute myeloid leukemia in humans.

Identification and Purification of Leukemic Stem-Like Cells in Acute Myeloid Leukemia Cell Line

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4734-4734
Author(s):  
Miaorong She ◽  
Xingqing Niu ◽  
Xilin Chen ◽  
Guo Kunyuan ◽  
Maohua Zhou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Cell Line ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Leukemic Stem Cells ◽  
Self Renewal ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is initiated and maintained by a rare population of (leukemic stem cells) LSCs. LSCs play the central role in the relapse and refractory of AML and highlight the critical need for the new therapeutic strategies to directly target the LSC population for ultimately curing leukemia which is it is important to identify and study LSCs. However, relatively little is known about the unique molecular mechanisms of survival and self-renewal of LSCs because of very small number of LSCs in bone marrow. In this study, we investigated whether established leukemia cell lines contain LSCs. We showed that leukemia cell line contain leukemic stem-like cells which have been phenotypically restricted within the CD34+CD38− fraction. We demonstrated that CD34+CD38− cells could generate CD34+CD38+ cells in culture medium and had proliferation function. Moreover, CD34+CD38− cells had self-renewal potential both in vitro soft agar colonies formation assay and in vivo NOD/SCID mouse xenotransplant model serial transplantation. Furthermore, CD34+CD38− cells isolated from leukemia cell line were found resistant to conventional chemotherapy and NK cells-mediated cytotoxicity and these were related to up-regulation of ABCG2 and MRP-1 and antiapoptotic proteins of Bcl2. Down-regulation of NKG2D ligand also played a critical role in NK cytotoxicity resistance. Taken together, our studies provide a novel cell model for leukemic stem cells research. Our data also shed light on mechanism of double resistant to resistant to chemotherapy and NK cell immunotherapy, which was helpful for developing novel effective strategies for LSCs.

The Apoptosis of Acute Myeloid Leukemia Cell Line (SHI-1 cells) Induced by Bortezomib In Vitro

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4382-4382
Author(s):  
Mingzhen Yang ◽  
Xiaoyu Zhang ◽  
Zhenqi Huang ◽  
Qingsheng Li ◽  
Lin Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Protein Expression ◽  
Proteasome Inhibitor ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Leukemia Cell ◽  
Myelogenous Leukemia ◽  
Leukemia Cell Line ◽  
Leukemia Cells ◽  
Acute Myeloid

Abstract Abstract 4382 Background: The proteasome plays a critical role in the regulation of many cellular processes, including the cell cycle and tumor growth. The proteasome inhibitor Bortezomib has been used in multiple myeloma and other lymphoid malignancies because of its antitumor activity. Here we investigated the induction of apoptosis by proteasome inhibitor Bortezomib in human acute myeloid leukemia (AML) cell lines SHI-1 cells and try to explore the mechanism of anti-leukemia. Method: We incubated SHI-1 leukemic cells with different concentration of bortezomib. cell proliferation was detected with MTT, apoptosis was measured by FCM, the protein expression of PI3K and p-Akt were determined by Western blot. Result: 0.5ug/ml bortezomib suppressed SHI-1 cells proliferation and induced SHI-1 cells apoptosis after incubated 24hr, 100ug/ml bortezomib suppressed 61.7% SHI-1 cells proliferation. Apoptosis increased obviously with the increasing bortezomib concentration and the culture time, about 39.77% SHI-1 cells were apoptosis when bortezomib concentration was 100ug/ml, the leukemia cell apoptosis was significant at 150ng/ml bortezomib, the protein expression of PI3K, and p-Akt gradually declined with bortezomib concentration increasing, The protein expression of PI3K and p-Akt in SHI-1 cells decreased 50.6% and 71.6% respectively at 100ug/ml bortezomib for 48hr.when 150ng/ml bortezomib incubated with leukemia cells for 24 hours, The protein expression of PI3K and p-Akt were lowest. Conclusion: Bortezomib could inhibit SHI-1 cells proliferation and induce leukemia cells apoptosis, and could down-regulate the expression of PI3K and p-Akt significantly, this might be the one of mechanisms that bortezomib induce SHI-1 cells apoptosis, we presume that bortezomib inhibit proliferation of acute myelogenous leukemia cells through effect of PI3K/Akt signaling pathways. Disclosures: No relevant conflicts of interest to declare.

Disulfiram, an clinically used anti-alcoholism drug has the potential to target acute myeloid leukemia cells in a copper-dependent manner in vivo

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5040-5040
Author(s):  
Bing Xu ◽  
Rongwei Li ◽  
Huijuan Dong ◽  
Feili Chen ◽  
Yuejian Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Specific Antigen ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Control Group ◽  
Acute Myeloid

Abstract Background Disulfiram(DS), an old drug clinically used for alcoholism, was reported to have antitumor effects, recent studies have found that Copper(Cu) can significantly enhance the DS-induced cell death in vitro in a variety of tumor cells. Our previous studies also demonstrated that disulfiram/copper (DS/Cu) couldtarget human leukemia cell lines(like KG1α,Molt4) through the activation of JNK, in vitro. However, there is few report about the ability of DS/Cu in killing cancer cells in vivo. Aims This study aims to explore the effect of DS/Cu on acute myeloid leukemia cell line KG1αin vivo and clarify the underlining mechanism. Methods 6-8 week old female NOD/SCID mice were sublethally irradiated with 2Gy X-ray the day before transplantation, followed by intravenous injection of KG1α cells (1×107 cells) suspended in 0.2 mL of PBS. 5 weeks after transplantation mice were randomly divided into three treatment groups: vehicle (0.9% saline), a combination of DS and Cu daily for 2 weeks, Ara-C alone twice before killing. Mice were sacrificed after 2 weeks treatment with tissues of spleen, liver, bone marrow being observed using histopathology method to detect the invasion of leukemia. The DS/Cu-induced p-c-jun activation was also examined by western blot using tissues of spleen, liver, bone marrow. Statistical analysis was carried out with one-way ANOVA to assess statistical significance (*p < 0.05). Results 4 weeks after transplantation, mice were dispirited with low appetite, down-bent gait, wrinkled fur, slow move, just like suffered from leukemia. What’s more, immature blasts like morphology similar to KG1α were found in the peripheral blood of the mice(11%±3.41). All the mice were sacrificed after 2 weeks treatment, mice in control group were observed with slightly larger spleen and liver with the morphology of invasion of leukemia such as a granular appearance than the other two groups. Histopathology examination showed that leukemia cells infiltrate liver, spleen and bone marrow, and the immunohistochemistry examination found that the leukemia cells in spleen, liver and bone marrow expressed human specific antigen CD45 with the highest expression level in the control group. Moreover, solid tumor could be observed in the peritoneal cavity of two mice in the control group with expression of human specific antigen CD45detected by immunohistochemistry examination. Western blot in this study showed DS/Cu complex induced phosphorylation of c-Jun expression in the spleen, liver and bone marrow. Conclusion DS/Cu complex could effectively target the acute myeloid leukemia cells in the acute leukemia NOD/SCID mice while inhibiting the invasion of leukemia to some extent, and the activation of JNK might play a functional role in DS/Cu mediated antileukemic effects. Disclosures: No relevant conflicts of interest to declare.

scholarly journals MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia

Blood ◽  
2012 ◽  
Vol 119 (21) ◽  
pp. 4992-5004 ◽  
Author(s):  
Xiao-Shuang Wang ◽  
Jia-Nan Gong ◽  
Jia Yu ◽  
Fang Wang ◽  
Xin-Hua Zhang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Myeloid Differentiation ◽  
Loss Of Function ◽  
Monocytic Differentiation ◽  
Granulocytic Differentiation ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Although microRNAs (miRNAs) are increasingly linked to various physiologic processes, including hematopoiesis, their function in the myeloid development is poorly understood. We detected up-regulation of miR-29a and miR-142-3p during myeloid differentiation in leukemia cell lines and CD34+ hematopoietic stem/progenitor cells. By gain-of-function and loss-of-function experiments, we demonstrated that both miRNAs promote the phorbol 12-myristate 13-acetate–induced monocytic and all-trans-retinoic acid-induced granulocytic differentiation of HL-60, THP-1, or NB4 cells. Both the miRNAs directly inhibited cyclin T2 gene, preventing the release of hypophosphorylated retinoblastoma and resulting in induction of monocytic differentiation. In addition, a target of miR-29a, cyclin-dependent kinase 6 gene, and a target of miR-142-3p, TGF-β–activated kinase 1/MAP3K7 binding protein 2 gene, are involved in the regulation of both monocytic and granulocytic differentiation. A significant decrease of miR-29a and 142-3p levels and an obvious increase in their target protein levels were also observed in blasts from acute myeloid leukemia. By lentivirus-mediated gene transfer, we demonstrated that enforced expression of either miR-29a or miR-142-3p in hematopoietic stem/progenitor cells from healthy controls and acute myeloid leukemia patients down-regulated expression of their targets and promoted myeloid differentiation. These findings confirm that miR-29a and miR-142-3p are key regulators of normal myeloid differentiation and their reduced expression is involved in acute myeloid leukemia development.

scholarly journals Functions of RNA N6-methyladenosine modification in acute myeloid leukemia

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Xue Zheng ◽  
Yuping Gong
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nuclear Export ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Gene Expression Regulation ◽  
Epigenetic Modification ◽  
Hematologic Malignancy ◽  
Critical Role ◽  
Leukemia Cell ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is a hematologic malignancy with an unfavorable prognosis. A better understanding of AML pathogenesis and chemotherapy resistance at the molecular level is essential for the development of new therapeutic strategies. Apart from DNA methylation and histone modification, RNA epigenetic modification, another layer of epigenetic modification, also plays a critical role in gene expression regulation. Among the more than 150 kinds of RNA epigenetic modifications, N6-methyladenosine (m6A) is the most prevalent internal mRNA modification in eukaryotes and is involved in various biological processes, such as circadian rhythms, adipogenesis, T cell homeostasis, spermatogenesis, and the heat shock response. As a reversible and dynamic modification, m6A is deposited on specific target RNA molecules by methyltransferases and is removed by demethylases. Moreover, m6A binding proteins recognize m6A modifications, influencing RNA splicing, stability, translation, nuclear export, and localization at the posttranscriptional level. Emerging evidence suggests that dysregulation of m6A modification is involved in tumorigenesis, including that of AML. In this review, we summarize the most recent advances regarding the biological functions and molecular mechanisms of m6A RNA methylation in normal hematopoiesis, leukemia cell proliferation, apoptosis, differentiation, therapeutic resistance, and leukemia stem cell/leukemia initiating cell (LSC/LIC) self-renewal. In addition, we discuss how m6A regulators are closely correlated with the clinical features of AML patients and may serve as new biomarkers and therapeutic targets for AML.

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