Inhibition of Unc-51-like Kinase 1 (ULK1) with Novel Small Molecular Inhibitor MRT68921 Preferentially Induces Apoptosis and Autophagy in FLT3-ITD- Mutated Acute Myeloid Leukemia

Abstract In normal karyotype acute myeloid leukemia (AML), FLT3-ITD mutation is associated with dismal prognosis with early relapse even after allogeneic stem cell transplantation. Unfortunately, to date small-molecule inhibitors of FLT3 have resulted in only partial and transient clinical responses with residual leukemic blasts acquiring resistance to FLT3 inhibitors. Therefore, elucidation of novel molecular targets should be necessary for effective eradication of FLT3-ITD AML cells. Evidences are accumulating on the functional roles of autophagy in the initiation and maintenance of AML as well as the development of drug resistance. Unc-51-like kinase 1 (ULK1) is a conserved serine-threonine kinase that plays a central role in the initiation of autophagy. Our group demonstrated that ULK1 is potentially involved in the development of resistance of AML leukemia stem cells to BET inhibitor, JQ1. The fact that ULK1 is the only conserved serine/threonine kinase in the autophagy cascade makes it a very attractive target for therapeutic development. However, the role of Ulk1 in FLT3-ITD AML remains unclear. In this study, we observed that MRT68921, a potent inhibitor of both ULK1 and ULK2, induced apoptotic cell death in FLT3-ITD-mutated AML cell lines (MV4-11, Molm13, U937/FLT3-ITD-muated) in a dose-dependent manner. However, apoptosis-inducing effect of MRT68921 was significantly lower in FLT3-WT AML (HL-60, U937). Cell death was accompanied with cleavage of caspases and PARP, which were partially blocked with caspase inhibitor z-VAD-fmk, indicating the caspase-dependent mechanism exists. MRT68921 treatment led to a notable decrease in the levels of phosphorylated (p) ATG13 (Ser 318) as well as total ULK1 and p-ULK1 (Ser 555). Interestingly, MRT68921 induced LC3-II lipidation, autophagosome, and GFP/LC3 punta formation, indicating autophagy was paradoxically activated in FLT3-ITD-mutated AML cells. AMPKa phosphorylation (T712) was increased in MTR68921-responsive cells. In contrast, autophagy induction was negligible to modest in FLT3-WT AML cells. Treatment of FLT3-ITD cells with autophagy inhibitors, 3-MA, bafilomycin A1, and hydroxychloroquine, markedly enhanced the MRT68921-induced apoptosis, strongly suggesting that prosurvival autophagy activation occurred with MRT68921 in FLT3-ITD cells. Reduction in the levels of total FLT3 and p-FLT3 protein were observed concurrently with downregulation of p-STAT5 in FLT3-ITD cells. Endoplasmic reticulum stress-associated proteins, p-PERK and p-eIF2a were also downregulated with MRT68921 in FLT3-ITD cells. Taken together, targeting the ULK1 pathway could be an effective therapeutic strategy for combating FLT3-ITD AML. Inhibition of prosurvival autophagy pathway could enhance the anti-leukemia effects of MRT68921. Disclosures No relevant conflicts of interest to declare.

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Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia

Blood ◽

10.1182/blood-2007-07-099325 ◽

2008 ◽

Vol 111 (5) ◽

pp. 2854-2865 ◽

Cited By ~ 95

Author(s):

Xue-Fei Huang ◽

Shao-Kai Luo ◽

Jie Xu ◽

Juan Li ◽

Duo-Rong Xu ◽

...

Keyword(s):

Cell Death ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Mononuclear Cells ◽

De Novo ◽

Apoptotic Cell ◽

Aurora Kinase ◽

Dependent Manner ◽

Aurora A ◽

Acute Myeloid

Previously, we and others showed that mitotic Aurora-A kinase (Aur-A) was required for accurate mitotic entry and proper spindle assembly. In this study, we found that expression of Aur-A was markedly elevated in bone marrow mononuclear cells (BMMCs) obtained from a significant portion of de novo acute myeloid leukemia (AML) patients. Targeting human primary AML cells with Aur-A kinase inhibitory VX-680 led to apoptotic cell death in a dose-dependent manner. Importantly, VX-680–induced cell death was preferentially higher in Aur-A-high primary leukemic blasts compared with Aur-A-low AML (P < .001) or normal BMMCs (P < .001), suggesting the possible pharmacologic window in targeting Aurora kinase among Aur-A-high VX-680–sensitive leukemia patients. VX-680–induced cell death in AML cell lines was accompanied by formation of monopolar mitotic spindles, G2/M phase arrest, decreased phosphorylated(p)-Akt-1, and increased proteolytic cleavage of procaspase-3 and poly(ADP)ribose polymerase. Notably, VX-680 increased Bax/Bcl-2 expression ratio, a favorable proapoptotic predictor for drug response and survival in AML. Lastly, VX-680 enhanced the cytotoxic effect of the chemotherapeutic agent etoposide (VP16) on AML cells. Together, we concluded that Aurora kinases were potentially therapeutic targets for AML and that Aur-A-high expression may serve as a differential marker for selective treatment.

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PKR-like Endoplasmic Reticulum Kinase Mediates Apoptosis Induced By Pharmacological AMP-Activated Protein Kinase Activation in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-123364 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2552-2552

Author(s):

Laury Poulain ◽

Adrien Grenier ◽

Johanna Mondesir ◽

Arnaud Jacquel ◽

Claudie Bosc ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Endoplasmic Reticulum Stress Response ◽

Ampk Activation ◽

Serine Threonine Kinase ◽

Threonine Kinase ◽

Amp Activated Protein Kinase ◽

Acute Myeloid

Acute myeloid leukemia (AML) is a myeloid progenitor-derived neoplasm of poor prognosis, particularly among the elderly, in whom age and comorbidities preclude the use of intensive therapies. Novel therapeutic approaches for AML are therefore critically needed. Adenosine monophosphate (AMP) activated protein kinase (AMPK) is a pleiotropic serine/threonine kinase promoting catabolism that represses anabolism and enhances autophagy in response to stress1. AMPK heterotrimers comprise catalytic α- and regulatory β- and γ-subunits, the latter harboring binding sites for AMP. Targets of AMPK include a host of metabolic pathway enzymes mediating carbohydrate, lipid and protein synthesis and metabolism. Accumulating evidence implicates AMPK in cancer biology, primarily as a tumor suppressor, although minimal AMPK activity may also be required for cancer cell growth under stress conditions2,3. Pharmacological activation of AMPK thus represents an attractive new strategy for targeting AML. We previously used the selective small molecule AMPK activator GSK621 to show that AMPK activation induces cytotoxicity in AML but not in normal hematopoietic cells, contingent on concomitant activation of the mammalian target of rapamycin complex 1 (mTORC1)4. However, the precise mechanisms of AMPK-induced AML cytotoxicity have remained unclear. We integrated gene expression profiling and bioinformatics proteomic analysis to identify the serine/threonine kinase PERK - one of the key effectors of the endoplasmic reticulum stress response - as a potential novel target of AMPK. We showed that PERK was directly phosphorylated by AMPK on at least two conserved residues (serine 439 and threonine 680) and that AMPK activators elicited a PERK/eIF2A signaling cascade independent of the endoplasmic reticulum stress response in AML cells. CRISPR/Cas9 depletion and complementation assays illuminated a critical role for PERK in apoptotic cell death induced by pharmacological AMPK activation. Indeed, GSK621 induced mitochondrial membrane depolarization and apoptosis in AML cells, an effect that was mitigated when cells were depleted of PERK or expressed PERK with a loss of function AMPK phosphorylation site mutation. We identified the mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) as a downstream target of the AMPK/PERK pathway, as its expression was enhanced in PERK knockdown AML cells. Moreover, selective pharmacologic activation of ALDH2 by the small molecule ALDA-1 recapitulated the protective effects of PERK depletion in the face of pharmacological AMPK activation. Corroborating the impact of the AMPK/PERK axis on mitochondrial apoptotic function, BH3 profiling showed marked Bcl-2 dependency in AML cells treated with GSK621. This dependency was abrogated in PERK-depleted cells, suggesting a role for PERK in mitochondrial priming to cell death. In vitro drug combination studies further demonstrated synergy between the clinical grade Bcl-2 inhibitor venetoclax (ABT-199) and each of four AMPK activators (GSK621, MK-8722, PF-06409577 and compound 991) in multiple AML cell lines. Finally, the addition of GSK621 to venetoclax enhanced anti-leukemic activity in primary AML patient samples ex vivo and in humanized mouse models in vivo. These findings together clarify the mechanisms of cytotoxicity induced by AMPK activation and suggest that combining pharmacologic AMPK activators with venetoclax may hold therapeutic promise in AML. References 1. Lin S-C, Hardie DG. AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metabolism. 2018;27(2):299-313. 2. Hardie DG. Molecular Pathways: Is AMPK a Friend or a Foe in Cancer? Clinical Cancer Research. 2015;21(17):3836-3840. 3. Jeon S-M, Hay N. The double-edged sword of AMPK signaling in cancer and its therapeutic implications. Arch. Pharm. Res. 2015;38(3):346-357. 4. Sujobert P, Poulain L, Paubelle E, et al. Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia. Cell Rep. 2015;11(9):1446-1457. Figure Disclosures Tamburini: Novartis pharmaceutical: Research Funding; Incyte: Research Funding.

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Inhibition of Bcl-xL overcomes polyploidy resistance and leads to apoptotic cell death in acute myeloid leukemia cells

Oncotarget ◽

10.18632/oncotarget.4306 ◽

2015 ◽

Vol 6 (25) ◽

pp. 21557-21571 ◽

Cited By ~ 13

Author(s):

Weihua Zhou ◽

Jie Xu ◽

Elise Gelston ◽

Xing Wu ◽

Zhengzhi Zou ◽

...

Keyword(s):

Cell Death ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Leukemia Cells ◽

Acute Myeloid Leukemia Cells ◽

Acute Myeloid

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Disulfiram, an Clinically Used Anti-Alcoholism Drug Has the Potential to Target Leukemia Stem and Progenitor Cells in a Copper-Dependent Manner

Blood ◽

10.1182/blood.v120.21.4088.4088 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4088-4088

Author(s):

Bing Xu ◽

Shiyun Wang ◽

Feili Chen ◽

Pengcheng Shi ◽

Jie Zha ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Mononuclear Cells ◽

Nuclear Translocation ◽

Conflicts Of Interest ◽

Therapeutic Option ◽

Flow Cytometric Analysis ◽

Dependent Manner ◽

Induced Apoptosis ◽

Acute Myeloid

Abstract Abstract 4088 Backgrounds Acute myeloid leukemia(AML) is a hierarchical disease initiating from a rare population of cells known as leukemia stem cells (LSCs), which are typically enriched in CD34+CD38- cells and presumed responsible for the relapse and refractory of AML. Moreover, current regimens may not effectively discriminate between normal and malignant cells. For this reason, it is important to identify therapies that can specifically target the LSC population without affecting normal cells. Disulfiram (DS) is an anti-alcoholism drug that has recently been indicated to show cytotoxic to multiple cancers including acute myeloid leukemia (AML) and the antineoplastic activity was enhanced in the present of copper (Cu). In the present study, we investigated the effect of DS/Cu on LSCs and further explored its mechanism. Methods and Results CD34+CD38- leukemia stem cell (LSC) enriched subpopulations were sorted from both KG1a cell lines and primary AML bone marrow or peripheral blood mononuclear cells (n=6) by fluoresce-activated cell sorting (FACS) analysis. Using MTT cell proliferation assay and Annexin-V/PI staining assay, We demonstrated that DS/Cu inhibited proliferation and induced apoptosis in CD34+CD38−KG1a cells (IC50= 0.788± 0.451 μM at 24h). With the increasing concentrations of DS (DS=0.05, 0.5, 5, 50μM), the apoptotic proportion increased from 7.2% to 89.5% at 24h. Apoptosis was also observed in CD34+CD38- primary AML cells and the exposure to DS/Cu (DS=0.01, 0.1, 1μM;Cu=0.5μM clearly inhibited the growth of AML-colony-forming units (CFUs) for both CD34+CD38-LSC enriched subpopulations (AML-CFUs decreased from 34.2% to 0% in KG1a cells), but was relatively sparing to normal hematopoietic progenitors. Further more, using flow cytometric analysis, western blot and RT-PCR, we identified that the change in redox status and redox-dependent signaling events play a crucial role in DS/Cu-induced apoptosis. We showed that DS/Cu(DS= 0.625,1.25,2.5,5μM, Cu=1μM) increased reactive oxygen species (ROS) and activated its downstream apoptosis-related SAPK/JNK pathway in association with blockade translocation of Nrf2 and expression of Nrf2-regulated genes in CD34+CD38−KG1a cells. Notably, blockade of ROS by glutathione precursor N-acetylcysteine (NAC)(10mM) strongly diminished DS/Cu mediated lethality and restored Nrf2 nuclear translocation and blocked JNK activation. Additionally, consistent with the ROS accumulation, we also seen that translocation of RelA/p65 and the expression of NF-κb-related gene, associated with abnormal apoptotic response of LSCs, were significantly inhibited by DS/Cu. Conclusion Taken together, we concluded that DS/Cu might selectively eradicate LSCs by induction of oxidatibe stress and blockade the NF-κb pathway and offers a potential therapeutic option in AML. Disclosures: No relevant conflicts of interest to declare.

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Treatment With G-CSF Reduces Acute Myeloid Leukemia (AML) Blasts Viability In Presence Of Bone Marrow Stroma

Blood ◽

10.1182/blood.v122.21.1422.1422 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1422-1422

Author(s):

Meritxell Nomdedeu ◽

Marta Pratcorona ◽

Marina Díaz-Beyá ◽

Xavier Calvo ◽

Mari Carmen Lara-Castillo ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Cell Viability ◽

Clinical Benefit ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Leukemic Cells ◽

Cell Counting ◽

Dependent Manner ◽

Dose Dependent ◽

Acute Myeloid

Abstract Background The simultaneous administration of G-CSF and chemotherapy as a priming strategy has resulted in a clinical benefit in determined subsets of patients diagnosed with acute myeloid leukemia (AML) (Löwenberg et al, NEJM 2003; Pabst T, et al, Blood 2012). However, the mechanism responsible for this anti-leukemic effect is not fully characterized. We hypothesize that the clinical benefit may occur at least partially by the effect of G-CSF on leukemic stem cells (LSC). Objective The main goal of this project was to determine the effect of G-CSF on primary AML samples in vitro, especially on LSCs. Methods and patients Peripheral blood mononuclear cells (PBMC) from 10 AML patients were treated with G-CSF at increasing doses, alone or in co-culture with HS-5 stroma cells. Cell viability (7-AAD -eBioscience- cell death exclusion and volumetric cell counting) and surface phenotype was determined by flow cytometry (FACSVerse, BD) 72 hours after treatment. Data were analyzed using the FlowJo (Trastar) software. For clonogenicity assays, AML primary samples were treated for 18 hours with G-CSF at increasing concentrations and cultured in H4034 Optimum MethoCult (StemCell Technologies) for 14 days. Colonies were counted based on cellularity and morphology criteria. Results G-CSF treatment showed no effect on cell viability of the bulk leukemic population or on the CD34 + immature subpopulation. A dose-dependent increase in CXCR4 surface expression was observed, reaching a 1.4-fold of change at the highest concentration of G-CSF (100 μg/mL). In contrast, treatment of leukemia cells with G-CSF in the presence of stroma cells reduced the overall cell viability. Thus, a 32% decrease of cell viability was measured at the highest concentration used (p = 0.0006), while no significant changes in the frequency of each leukemic subpopulations were observed. Clonogenic capacity was significantly reduced in a dose-dependent manner upon treatment with G-CSF, achieving a 41% reduction at the highest G-CSF concentration (100 μg/mL). Conclusions G-CSF reduces the viability of leukemic cells when these cells are in co-culture with the HS-5 stroma cell line, suggesting that the presence of stroma cells is required for the cytotoxical effect of G-CSF on the blast population. Interestingly, G-CSF treatment decreased the clonogenic capacity of AML samples, therefore suggesting that G-CSF exerts its effect at least partially on LSCs. Our findings support the design of studies to explore new strategies of chemotherapy priming in AML patients. Disclosures: No relevant conflicts of interest to declare.

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IGF2BP3 As an N6-Methyladenosine Reader Promotes Acute Myeloid Leukemia Progression By Regulating the Stability of Target RNA

Blood ◽

10.1182/blood-2021-148470 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4322-4322

Author(s):

Nan Zhang ◽

Jianchuan Deng ◽

Fuling Zhou

Keyword(s):

Acute Myeloid Leukemia ◽

Genetic Risk ◽

Myeloid Leukemia ◽

Poor Prognosis ◽

Target Genes ◽

Conflicts Of Interest ◽

Clinical Samples ◽

Dependent Manner ◽

High Genetic Risk ◽

Acute Myeloid

Abstract Background: N6-methyladenosine (m6A) is the most common post-transcriptional modification of eukaryotic mRNA. Recent evidence suggests that dysregulated m6A-associated proteins and m6A modifications play a pivotal role in the initiation and progression of diseases such as cancer. Here, we identified that IGF2BP3 is specifically overexpressed in acute myeloid leukemia (AML), which constitutes a subtype of this malignancy associated with poor prognosis and high genetic risk. Methods: Bioinformatics analysis of public databases was performed to screen the differentially expressed m6A regulators in AML. Clinical samples were collected to detect the expression of IGF2BP3 in AML by RT-qPCR. The effects of IGF2BP3 on the proliferation, apoptosis and cycle of AML cells were detected by CCK-8 and flow cytometry. RNA-seq was used to identify target genes of IGF2BP3 by integrating analysis with RIP-Seq, iCLIP-Seq and MeRIP-Seq data sets. Results:High expression of IGF2BP3 is closely associated with poor prognosis of AML and is higher in patients with high genetic risk group. IGF2BP3 was the lowest expressed in AML-M3 and the highest expressed in RUNX1 mutant type. IGF2BP3 is required for maintaining AML cell survival in an m6A-dependent manner, and knockdown of IGF2BP3 suppressed dramatically induces apoptosis, reduces proliferation and impaired leukemic capacity AML cells in vitro and in vivo. Mechanistically, IGF2BP3 interacts with RCC2 mRNA and stabilizes the expression of m6A-tagged RNA. Conclusions:We provided compelling evidence to demonstrate that m6A reader IGF2BP3 contributed to tumorigenesis and poor prognosis of AML, which can serve as a target to develop therapeutics for cancer treatment. Disclosures No relevant conflicts of interest to declare. Disclosures No relevant conflicts of interest to declare.

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The Synergistic Effect of DNA Methylation Inhibitor 5-Azacytidine and Bcl-2 Signaling Blockade ABT-737 Combination Treatment Induce Apoptosis In AML

Blood ◽

10.1182/blood.v116.21.3311.3311 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3311-3311

Author(s):

Yuexi Shi ◽

Twee Tsao ◽

Hongbo Lu ◽

Sergej Konoplev ◽

Wendy D. Schober ◽

...

Keyword(s):

Bone Marrow ◽

Cell Death ◽

Acute Myeloid Leukemia ◽

Cell Lines ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Cytotoxic Agents ◽

Leukemia Cells ◽

Clinical Activity ◽

Acute Myeloid

Abstract Abstract 3311 Bcl-2 family proteins are key regulators of apoptosis. Aberrations in Bcl2 levels are known to promote tumorigenesis and chemoresistance. Thus strategies to target Bcl2 will likely provide effective therapies for malignancies such as acute myeloid leukemia (AML). ABT-737 is a small molecule BH3 mimetic that binds tightly to a hydrophobic cleft on Bcl-2 and Bcl-XL and exerts its proapoptotic function by preventing antiapoptotic Bcl-2 family members from sequestering activating BH3 proteins (Oltersdorf et al., Nature 2005). We have reported that ABT-737 effectively kills acute myeloid leukemia blast, progenitor, and stem cells without affecting normal hematopoietic cells. ABT-737 induces the disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway (Konopleva et al., Cancer Cell 2006). The ABT-737 related clinical compound, ABT-263, is undergoing Phase I/II studies in chronic lymphocytic leukemia, with initial signs of clinical activity. However, the main side effect is thrombocytopenia resulting from inhibition of Bcl-XL. Hence, combinations of ABT-737 with non-cytotoxic agents are desirable to take full advantage of ABT236's unique spectrum of biophysical and preclinical activities. In this project, we studied pharmacologic interactions between ABT-737 and the DNA methyltransferase inhibitor 5-azacytidine (5-azaC). 5-azaC is a cytidine analog with clinical activity in myelodysplastic syndromes (MDS) and in AML. Since recent studies indicate that 5-azaC induce DNA damage in p53-dependent fashion, we tested the hypothesis that the pro-apoptotic effects of 5-azaC/ABT-737 combination are related to non-redundant activation of BH3-only proteins and mitochondrial apoptosis in AML cells with wt p53. In vitro, 5-azaC and ABT-737 in combination for 72 hrs induced growth inhibition and apoptosis in AML cell lines OCI-AML3, MOLM-13 and U937 in a highly synergistic, dose-dependent fashion, with combination indices (CIs) ranging from 0.1 to 0.22. These effects were observed even at low concentrations (5-azaC 100nM and ABT-737 10nM, at 10:1 ratio). In contrast, no synergistic apoptosis was seen in p53-null HL-60 cells. Likewise, ABT-737/5-azaC induced apoptosis in a synergistic fashion in OCI-AML3 cells infected with vector control shRNA (CI=0.04) but failed to induce cell death in OCI-AML3 p53 shRNA cells, indicating critical p53-dependent mechanisms of cell death. In primary AML samples sensitive to ABT-737 alone (n=3), synergistic and additive effects were seen. The combined effects of 5-azaC and ABT-737 were further investigated in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice injected with cells from a patient with primary refractory AML. Seven days after leukemia transplantation, mice were treated with vehicle, ABT-737 (intraperitoneally (IP), 75mg/kg/day for 10 days), 5-azacytidine (IP, 4mg/kg/day for 5 days) or with the combination. Engraftment of patient leukemia cells was analyzed by the immunohistochemical detection of CD45-positive cells in bone marrow and spleen seven weeks after transplantation. Both, ABT-737 and 5azaC each exerted anti-leukemic effects, as evidenced by significant reduction in leukemia cells in bone marrow and spleen (10% and 3% CD45+ cells detectable in 1/3 mice in ABT-737 and 5-azaC groups, respectively), no CD45+ AML cells were detected in organs of 3/3 mice treated with the combination. No overt hemorrhage was detected in the animals. In summary, the combination of 5-azaC and ABT-737 induces synergistic cells death in AML cell lines and in a subset of primary AML samples in a p53-dependent fashion. The mechanisms of this pharmacologic interactions including the p53-dependent upregulation of BH3-only proteins, described by us for ABT-737/MDM2 inhibitor combinations, are currently under investigation. Results suggest that this therapeutic strategy can be successfully utilized in AML patients with low mutation rate and unimpaired signaling of p53. Disclosures: No relevant conflicts of interest to declare.

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A New Strategy to Target Acute Myeloid Leukemia Stem and Progenitor Cells Using Chidamide, a Histone Deacetylase Inhibitor

Blood ◽

10.1182/blood.v126.23.4925.4925 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4925-4925

Author(s):

Bing Xu ◽

Yin Li ◽

Kai Chen ◽

Yong Zhou ◽

Yiren Xiao ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Histone Deacetylase ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Hdac Inhibitors ◽

Mechanistic Study ◽

G1 Arrest ◽

Dependent Manner ◽

Mitochondria Membrane Potential ◽

Acute Myeloid

Abstract Leukemia stem cells (LSCs) are responsible for treatment failure and relapse in acute myeloid leukemia (AML). Therefore, development of novel LSCs-targeting therapeutic strategies is of crucial clinical importance to improve the treatment outcomes of AML. Histone deacetylase (HDAC) inhibitors have emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer. HDAC inhibitors have shown potent and specific anticancer stem cell activities in preclinical studies. Chidamide, a novel benzamide-type selectively HDAC inhibitor, has been reported to induce G1 arrest and apoptosis in the relatively mature progenitor population, whereas its effect on primitive LSCs has not been clarified. In this study, we demonstrated that chidamide specifically induces apoptosis in LSC-like cells and primary AML CD34+ cells in a concentration- and time-dependent manner. Our further molecular mechanistic study uncovered that chidamide induces LSCs death by activation of reactive oxygen species (ROS). It compromises the mitochondria membrane potential, modulates anti-apoptotic and pro-apoptotic proteins in BCL2 family and activates caspase-3 leading to PARP degradation. Meanwhile, chidamide activates CD40 and modulates its downstream signaling pathways, JNK and NFκB. The results of this study suggest that chidamide may be a novel LSC-targeting agent for AML therapeutics. Disclosures No relevant conflicts of interest to declare.

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Decitabine Combined with Minimally Myelosuppressive Therapy for Induction of Remission of Pediatric High-Risk Acute Myeloid Leukemia with Chromosome 5q Deletion. a Report of Three Cases

Blood ◽

10.1182/blood-2021-151594 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4427-4427

Author(s):

Shengqin Cheng ◽

Peifang Xiao ◽

Juxiang Wang ◽

Li Gao ◽

Jiajia Zheng ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Hematopoietic Cell Transplantation ◽

Conflicts Of Interest ◽

Conditioning Regimen ◽

Remission Induction ◽

Chromosome 5Q ◽

Dismal Prognosis ◽

Pediatric Aml ◽

Acute Myeloid

Abstract Cases of pediatric acute myeloid leukemia (AML) with complex karyotypes including chromosome 5 abnormalities are rare and have a dismal prognosis. Management of AML with monosomy 5/del(5q) has not been uniform. We treated three adolescents with this AML subtype with combined low-dose cytarabine and mitoxantrone, concurrent with decitabine and G-CSF, for remission induction. Decitabine was also included in the conditioning regimen before hematopoietic cell transplantation (HCT). All three patients attained complete remission after treatment with this combination. The treatment was well tolerated, and the patients are alive and free of disease at 3.6, 3.2, and 3.0 years after HCT, respectively. Our experience suggests that HCT is required for the eradication of pediatric AML, and possibly MDS, with complex karyotypes including del(5q). Decitabine combined with regimens of low myelotoxicity for remission induction represents an alternative approach to decrease the risk of complications associated with post-remission chemotherapy before HCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Antitumor Effect of Pomolic Acid in Acute Myeloid Leukemia Cells Involves Cell Death, Decreased Cell Growth and Topoisomerases Inhibition

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180412120128 ◽

2019 ◽

Vol 18 (10) ◽

pp. 1457-1468

Author(s):

Michelle X.G. Pereira ◽

Amanda S.O. Hammes ◽

Flavia C. Vasconcelos ◽

Aline R. Pozzo ◽

Thaís H. Pereira ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Acute Myeloid Leukemia ◽

Cell Lines ◽

Myeloid Leukemia ◽

Natural Compound ◽

Dna Topoisomerases ◽

Human Dna ◽

Pomolic Acid ◽

Acute Myeloid

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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