Abstract 94: Pla2g4a: A new cell cycle related gene in patients with non-M3/NPM1 wildtype acute myeloid leukemia

Background: Acute myeloid leukemia (AML) represents the largest number of annual deaths from hematologic malignancy. In the United States, it was estimated that 21.380 individuals would be diagnosed with AML and 49.5% of patients would die in 2017. Therefore, the search for novel compounds capable of increasing the overall survival rate to the treatment of AML cells is urgent. Objectives: To investigate the cytotoxicity effect of the natural compound pomolic acid (PA) and to explore the mechanism of action of PA in AML cell lines with different phenotypes. Methods: Three different AML cell lines, HL60, U937 and Kasumi-1 cells with different mechanisms of resistance were used to analyze the effect of PA on the cell cycle progression, on DNA intercalation and on human DNA topoisomerases (hTopo I and IIα) in vitro studies. Theoretical experiments of the inhibition of hTopo I and IIα were done to explore the binding modes of PA. Results: PA reduced cell viability, induced cell death, increased sub-G0/G1 accumulation and activated caspases pathway in all cell lines, altered the cell cycle distribution and inhibited the catalytic activity of both human DNA topoisomerases. Conclusion: Finally, this study showed that PA has powerful antitumor activity against AML cells, suggesting that this natural compound might be a potent antineoplastic agent to improve the treatment scheme of this neoplasm.

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ATF3 coordinates serine and nucleotide metabolism to drive cell cycle progression in acute myeloid leukemia

Molecular Cell ◽

10.1016/j.molcel.2021.05.008 ◽

2021 ◽

Author(s):

Daniela Di Marcantonio ◽

Esteban Martinez ◽

Joice S. Kanefsky ◽

Jacklyn M. Huhn ◽

Rashid Gabbasov ◽

...

Keyword(s):

Cell Cycle ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cell Cycle Progression ◽

Nucleotide Metabolism ◽

Cycle Progression ◽

Acute Myeloid

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Identification and validation of obesity-related gene LEP methylation as a prognostic indicator in patients with acute myeloid leukemia

Clinical Epigenetics ◽

10.1186/s13148-021-01013-9 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Ting-juan Zhang ◽

Zi-jun Xu ◽

Yu Gu ◽

Ji-chun Ma ◽

Xiang-mei Wen ◽

...

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Prognostic Indicator ◽

The Cancer Genome Atlas ◽

Related Gene ◽

Targeted Bisulfite Sequencing ◽

Specific Pcr ◽

Frequent Event ◽

Acute Myeloid

Abstract Background Obesity confers enhanced risk for multiple diseases including cancer. The DNA methylation alterations in obesity-related genes have been implicated in several human solid tumors. However, the underlying role and clinical implication of DNA methylation of obesity-related genes in acute myeloid leukemia (AML) has yet to be elucidated. Results In the discovery stage, we identified that DNA methylation-associated LEP expression was correlated with prognosis among obesity-related genes from the databases of The Cancer Genome Atlas. In the validation stage, we verified that LEP hypermethylation was a frequent event in AML by both targeted bisulfite sequencing and real-time quantitative methylation-specific PCR. Moreover, LEP hypermethylation, correlated with reduced LEP expression, was found to be associated with higher bone marrow blasts, lower platelets, and lower complete remission (CR) rate in AML. Importantly, survival analysis showed that LEP hypermethylation was significantly associated with shorter overall survival (OS) in AML. Moreover, multivariate analysis disclosed that LEP hypermethylation was an independent risk factor affecting CR and OS among non-M3 AML. By clinical and bioinformatics analysis, LEP may be also regulated by miR-517a/b expression in AML. Conclusions Our findings indicated that the obesity-related gene LEP methylation is associated with LEP inactivation, and acts as an independent prognostic predictor in AML.

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Octadecyloxyethyl Adefovir Exhibits Potent in vitro and in vivo Cytotoxic Activity and Has Synergistic Effects with Ara-C in Acute Myeloid Leukemia

Chemotherapy ◽

10.1159/000491705 ◽

2018 ◽

Vol 63 (4) ◽

pp. 225-237 ◽

Cited By ~ 1

Author(s):

Haytham Khoury ◽

Ruijuan He ◽

Aaron Schimmer ◽

James R. Beadle ◽

Karl Y. Hostetler ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Acute Myeloid Leukemia ◽

Cell Cycle Arrest ◽

Clinical Benefit ◽

Myeloid Leukemia ◽

Mouse Bone Marrow ◽

Medical Needs ◽

Cycle Arrest ◽

Acute Myeloid

Acute myeloid leukemia (AML) continues to be a deadly disease, with only 50–70% of patients achieving complete remission and less than 30% of adults having sustained long-term remissions. In order to address these unmet medical needs, we carried out a high-throughput screen of an in-house library of on- and off-patent drugs with the OCI/AML-2 cell line. Through this screen, we discovered adefovir dipivoxil (adefovir-DP) as being active against human AML. In addition to adefovir-DP, there are second-generation formulations of adefovir, including octadecyloxyethyl adefovir (ODE-adefovir) and hexadecyloxypropyl adefovir (HDP-adefovir), which were designed to overcome the pharmacokinetic problems of the parent compound adefovir. Given the known clinical benefit of nucleoside analogs for the treatment of AML, we undertook studies to evaluate the potential benefit of adefovir-based molecules. In AML cell lines and patient samples, adefovir-DP and ODE-adefovir were highly potent, whereas HDP-adefovir was significantly less active. Interestingly, ODE-adefovir was remarkably less toxic than adefovir-DP towards normal hematopoietic cells. In addition, ODE-adefovir at a dose of 15 mg/kg/day showed potent activity against human AML in a NOD/SCID mouse model, with a reduction of human leukemia in mouse bone marrow of > 40% in all mice tested within 20 days of treatment. Based on its chemical structure, we hypothesized that the cytotoxicity of ODE-adefovir toward AML was through cell cycle arrest and DNA damage. Indeed, ODE-adefovir treatment induced cell cycle arrest in the S phase and increased levels of pH2Ax, indicating the induction of DNA damage. Furthermore, there was an increase in phospho-p53, transactivation of proapoptotic genes and activation of the intrinsic apoptotic pathway. Subsequent investigation unveiled strong synergism between ODE-adefovir and ara-C, making their coadministration of potential clinical benefit. Expression of MRP4, a nucleoside transporter, appeared to influence the response of AML cells to ODE-adefovir, as its inhibition potentiated ODE-adefovir killing. Taken together, our findings indicate that clinical development of ODE-adefovir or related compounds for the treatment of AML is warranted.

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Nuclear phospholipase C β1, regulation of the cell cycle and progression of acute myeloid leukemia

Advances in Enzyme Regulation ◽

10.1016/j.advenzreg.2005.02.001 ◽

2005 ◽

Vol 45 (1) ◽

pp. 126-135 ◽

Cited By ~ 12

Author(s):

Lucio Cocco ◽

Lucia Manzoli ◽

Giandomenico Palka ◽

Alberto M. Martelli

Keyword(s):

Cell Cycle ◽

Acute Myeloid Leukemia ◽

Phospholipase C ◽

Myeloid Leukemia ◽

Acute Myeloid

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Loss of ISWI ATPase SMARCA5 (SNF2H) in Acute Myeloid Leukemia Cells Inhibits Proliferation and Chromatid Cohesion

International Journal of Molecular Sciences ◽

10.3390/ijms21062073 ◽

2020 ◽

Vol 21 (6) ◽

pp. 2073

Author(s):

Tomas Zikmund ◽

Helena Paszekova ◽

Juraj Kokavec ◽

Paul Kerbs ◽

Shefali Thakur ◽

...

Keyword(s):

Cell Cycle ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cell Cycle Progression ◽

Mitotic Division ◽

Cycle Progression ◽

Hematopoietic Stem ◽

Chromatid Cohesion ◽

Acute Myeloid Leukemia Cells ◽

Acute Myeloid

ISWI chromatin remodeling ATPase SMARCA5 (SNF2H) is a well-known factor for its role in regulation of DNA access via nucleosome sliding and assembly. SMARCA5 transcriptionally inhibits the myeloid master regulator PU.1. Upregulation of SMARCA5 was previously observed in CD34+ hematopoietic progenitors of acute myeloid leukemia (AML) patients. Since high levels of SMARCA5 are necessary for intensive cell proliferation and cell cycle progression of developing hematopoietic stem and progenitor cells in mice, we reasoned that removal of SMARCA5 enzymatic activity could affect the cycling or undifferentiated state of leukemic progenitor-like clones. Indeed, we observed that CRISPR/cas9-mediated SMARCA5 knockout in AML cell lines (S5KO) inhibited the cell cycle progression. We also observed that the SMARCA5 deletion induced karyorrhexis and nuclear budding as well as increased the ploidy, indicating its role in mitotic division of AML cells. The cytogenetic analysis of S5KO cells revealed the premature chromatid separation. We conclude that deleting SMARCA5 in AML blocks leukemic proliferation and chromatid cohesion.

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Axolotl Ambystoma mexicanum extract induces cell cycle arrest and differentiation in human acute myeloid leukemia HL-60 cells

Tumor Biology ◽

10.1177/1010428320954735 ◽

2020 ◽

Vol 42 (9) ◽

pp. 101042832095473

Author(s):

Sherif Suleiman ◽

Riccardo Di Fiore ◽

Analisse Cassar ◽

Melissa Marie Formosa ◽

Pierre Schembri-Wismayer ◽

...

Keyword(s):

Cell Cycle ◽

Acute Myeloid Leukemia ◽

Anticancer Activity ◽

Cell Cycle Arrest ◽

Crude Extract ◽

Myeloid Leukemia ◽

Ambystoma Mexicanum ◽

Cycle Arrest ◽

Human Acute Myeloid Leukemia ◽

Acute Myeloid

Acute myeloid leukemia is the most common form of acute leukemia in adults, constituting about 80% of cases. Although remarkable progress has been made in the therapeutic scenario for patients with acute myeloid leukemia, research and development of new and effective anticancer agents to improve patient outcome and minimize toxicity is needed. In this study, the antitumor activity of axolotl (AXO) Ambystoma mexicanum crude extract was assessed in vitro on the human acute myeloid leukemia HL-60 cell line. The anticancer activity was evaluated in terms of ability to influence proliferative activity, cell viability, cell cycle arrest, and differentiation. Moreover, gene expression analysis was performed to evaluate the genes involved in the regulation of these processes. The AXO crude extract exhibited antiproliferative but not cytotoxic activities on HL-60 cells, with cell cycle arrest in the G0/G1 phase. Furthermore, the AXO-treated HL-60 cells showed an increase in both the percentage of nitroblue tetrazolium positive cells and the expression of CD11b, whereas the proportion of CD14-positive cells did not change, suggesting that extract is able to induce differentiation toward the granulocytic lineage. Finally, the treatment with AXO extract caused upregulation of CEBPA, CEBPB, CEBPE, SPI1, CDKN1A, and CDKN2C, and downregulation of c-MYC. Our data clearly show the potential anticancer activity of Ambystoma mexicanum on HL-60 cells and suggest that it could help develop promising therapeutic agents for the treatment of acute myeloid leukemia.

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Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML)

Blood ◽

10.1182/blood-2002-10-3062 ◽

2003 ◽

Vol 101 (8) ◽

pp. 3142-3149 ◽

Cited By ~ 184

Author(s):

Yinghui Guan ◽

Brigitte Gerhard ◽

Donna E. Hogge

Keyword(s):

Cell Cycle ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Active Cell ◽

Leukemic Cells ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Acute Myeloid

Abstract Although many acute myeloid leukemia (AML) colony-forming cells (CFCs) and long-term culture–initiating cells (LTC-ICs) directly isolated from patients are actively cycling, quiescent progenitors are present in most samples. In the current study,3H-thymidine (3H-Tdr) suicide assays demonstrated that most NOD/SCID mouse leukemia-initiating cells (NOD/SL-ICs) are quiescent in 6 of 7 AML samples. AML cells in G0, G1, and S/G2+M were isolated from 4 of these samples using Hoechst 33342/pyroninY staining and cell sorting. The progenitor content of each subpopulation was consistent with the 3H-Tdr suicide results, with NOD/SL-ICs found almost exclusively among G0 cells while the cycling status of AML CFCs and LTC-ICs was more heterogeneous. Interestingly, after 72 hours in serum-free culture with or without Steel factor (SF), Flt-3 ligand (FL), and interleukin-3 (IL-3), most G0 AML cells entered active cell cycle (percentage of AML cells remaining in G0 at 72 hours, 1.2% to 37%, and 0% to 7.6% in cultures without and with growth factors [GFs], respectively) while G0 cells from normal lineage-depleted bone marrow remained quiescent in the absence of GF. All 4 AML samples showed evidence of autocrine production of 2 or more of SF, FL, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, 3 of 4 samples contained an internal tandem duplication of theFLT3 gene. In summary, quiescent leukemic cells, including NOD/SL-ICs, are present in most AML patients. Their spontaneous entry into active cell cycle in short-term culture might be explained by the deregulated GF signaling present in many AMLs.

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