scholarly journals Functional Genetic Variants in ATG10 Are Associated with Acute Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1344
Author(s):  
Isabel Castro ◽  
Belém Sampaio-Marques ◽  
Anabela C. Areias ◽  
Hugo Sousa ◽  
Ângela Fernandes ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Genetic Variants ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Metabolic Reprogramming ◽  
Peripheral Blood Mononuclear ◽  
Increased Risk ◽  
And Gender ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is the most common acute leukemia, characterized by a heterogeneous genetic landscape contributing, among others, to the occurrence of metabolic reprogramming. Autophagy, a key player on metabolism, plays an essential role in AML. Here, we examined the association of three potentially functional genetic polymorphisms in the ATG10 gene, central for the autophagosome formation. We screened a multicenter cohort involving 309 AML patients and 356 healthy subjects for three ATG10 SNPs: rs1864182T>G, rs1864183C>T and rs3734114T>C. The functional consequences of the ATG10 SNPs in its canonical function were investigated in vitro using peripheral blood mononuclear cells from a cohort of 46 healthy individuals. Logistic regression analysis adjusted for age and gender revealed that patients carrying the ATG10rs1864182G allele showed a significantly decreased risk of developing AML (OR [odds ratio] = 0.58, p = 0.001), whereas patients carrying the homozygous ATG10rs3734114C allele had a significantly increased risk of developing AML (OR = 2.70, p = 0.004). Functional analysis showed that individuals carrying the ATG10rs1864182G allele had decreased autophagy when compared to homozygous major allele carriers. Our results uncover the potential of screening for ATG10 genetic variants in AML prevention strategies, in particular for subjects carrying other AML risk factors such as elderly individuals with clonal hematopoiesis of indeterminate potential.

scholarly journals Development of siRNA-Loaded Lipid Nanoparticles Targeting Long Non-Coding RNA LINC01257 as a Novel and Safe Therapeutic Approach for t(8;21) Pediatric Acute Myeloid Leukemia

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1681
Author(s):  
Patrick Connerty ◽  
Ernest Moles ◽  
Charles E. de Bock ◽  
Nisitha Jayatilleke ◽  
Jenny L. Smith ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Sirna Delivery ◽  
Standard Of Care ◽  
Lipid Nanoparticles ◽  
Protein Product ◽  
Peripheral Blood Mononuclear ◽  
Acute Myeloid

Standard of care therapies for children with acute myeloid leukemia (AML) cause potent off-target toxicity to healthy cells, highlighting the need to develop new therapeutic approaches that are safe and specific for leukemia cells. Long non-coding RNAs (lncRNAs) are an emerging and highly attractive therapeutic target in the treatment of cancer due to their oncogenic functions and selective expression in cancer cells. However, lncRNAs have historically been considered ‘undruggable’ targets because they do not encode for a protein product. Here, we describe the development of a new siRNA-loaded lipid nanoparticle for the therapeutic silencing of the novel oncogenic lncRNA LINC01257. Transcriptomic analysis of children with AML identified LINC01257 as specifically expressed in t(8;21) AML and absent in healthy patients. Using NxGen microfluidic technology, we efficiently and reproducibly packaged anti-LINC01257 siRNA (LNP-si-LINC01257) into lipid nanoparticles based on the FDA-approved Patisiran (Onpattro®) formulation. LNP-si-LINC01257 size and ζ-potential were determined by dynamic light scattering using a Malvern Zetasizer Ultra. LNP-si-LINC01257 internalization and siRNA delivery were verified by fluorescence microscopy and flow cytometry analysis. lncRNA knockdown was determined by RT-qPCR and cell viability was characterized by flow cytometry-based apoptosis assay. LNP-siRNA production yielded a mean LNP size of ~65 nm with PDI ≤0.22 along with a >85% siRNA encapsulation rate. LNP-siRNAs were efficiently taken up by Kasumi-1 cells (>95% of cells) and LNP-si-LINC01257 treatment was able to successfully ablate LINC01257 expression which was accompanied by a significant 55% reduction in total cell count following 48 h of treatment. In contrast, healthy peripheral blood mononuclear cells (PBMCs), which do not express LINC01257, were unaffected by LNP-si-LINC01257 treatment despite comparable levels of LNP-siRNA uptake. This is the first report demonstrating the use of LNP-assisted RNA interference modalities for the silencing of cancer-driving lncRNAs as a therapeutically viable and non-toxic approach in the management of AML.

scholarly journals Treatment with interleukin-3 plus granulocyte-macrophage colony- stimulating factors improves the selectivity of Ara-C in vitro against acute myeloid leukemia blasts

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2674-2679
Author(s):  
K Bhalla ◽  
C Holladay ◽  
Z Arlin ◽  
S Grant ◽  
AM Ibrado ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Combined Treatment ◽  
Hematopoietic Growth Factors ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony ◽  
Acute Myeloid

Hematopoietic growth factors (HGFs) interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) individually have been shown to increase the percentage of acute myeloid leukemia (AML) blasts in S phase and enhance the cytotoxic effects of Ara-C against these blasts in culture. We compared in vitro the effects of a combined treatment with GM-CSF (10 ng/mL) plus IL-3 (10 ng/mL) on the metabolism and cytotoxicity of Ara-C in normal bone marrow mononuclear cells (NBMMC) and AML blasts. NBMMC from six healthy volunteers and AML blasts from 10 patients were incubated for 20 hours with or without IL- 3 plus GM-CSF, followed by a concurrent treatment with Ara-C for 4 additional hours. Exposure to the HGFs and Ara-C produced significantly higher intracellular Ara-CTP levels as well as higher Ara-CTP/dCTP pool ratios in AML blasts as compared with NBMMC. Treatment with HGFs resulted in [3H] Ara-C DNA incorporation that was significantly higher in AML blasts versus NBMMC. This selective improvement of Ara-C metabolism in AML blasts was associated with an enhanced Ara-C-mediated leukemia colony-forming unit (CFU) growth inhibition. In contrast, exposure to HGFs resulted in an improved colony growth of normal CFU granulocyte-monocyte and CFU-granulocyte, erythroid, monocyte, megakaryocyte. These in vitro studies indicate that a combined treatment with IL-3 plus GM-CSF may improve the selectivity of Ara-C against AML blasts.

scholarly journals Treatment with interleukin-3 plus granulocyte-macrophage colony- stimulating factors improves the selectivity of Ara-C in vitro against acute myeloid leukemia blasts

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2674-2679 ◽  
Author(s):  
K Bhalla ◽  
C Holladay ◽  
Z Arlin ◽  
S Grant ◽  
AM Ibrado ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Combined Treatment ◽  
Hematopoietic Growth Factors ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony ◽  
Acute Myeloid

Abstract Hematopoietic growth factors (HGFs) interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) individually have been shown to increase the percentage of acute myeloid leukemia (AML) blasts in S phase and enhance the cytotoxic effects of Ara-C against these blasts in culture. We compared in vitro the effects of a combined treatment with GM-CSF (10 ng/mL) plus IL-3 (10 ng/mL) on the metabolism and cytotoxicity of Ara-C in normal bone marrow mononuclear cells (NBMMC) and AML blasts. NBMMC from six healthy volunteers and AML blasts from 10 patients were incubated for 20 hours with or without IL- 3 plus GM-CSF, followed by a concurrent treatment with Ara-C for 4 additional hours. Exposure to the HGFs and Ara-C produced significantly higher intracellular Ara-CTP levels as well as higher Ara-CTP/dCTP pool ratios in AML blasts as compared with NBMMC. Treatment with HGFs resulted in [3H] Ara-C DNA incorporation that was significantly higher in AML blasts versus NBMMC. This selective improvement of Ara-C metabolism in AML blasts was associated with an enhanced Ara-C-mediated leukemia colony-forming unit (CFU) growth inhibition. In contrast, exposure to HGFs resulted in an improved colony growth of normal CFU granulocyte-monocyte and CFU-granulocyte, erythroid, monocyte, megakaryocyte. These in vitro studies indicate that a combined treatment with IL-3 plus GM-CSF may improve the selectivity of Ara-C against AML blasts.

Centrosome aberrations in acute myeloid leukemia are correlated with cytogenetic risk profile

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 289-291 ◽  
Author(s):  
Kai Neben ◽  
Christian Giesecke ◽  
Silja Schweizer ◽  
Anthony D. Ho ◽  
Alwin Krämer
Keyword(s):  
Acute Myeloid Leukemia ◽  
Genetic Instability ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Risk Groups ◽  
Risk Profile ◽  
Chromosome Count ◽  
Peripheral Blood Mononuclear ◽  
Possible Cause ◽  
Acute Myeloid

Abstract Genetic instability is a common feature in acute myeloid leukemia (AML). Centrosome aberrations have been described as a possible cause of aneuploidy in many human tumors. To investigate whether centrosome aberrations correlate with cytogenetic findings in AML, we examined a set of 51 AML samples by using a centrosome-specific antibody to pericentrin. All 51 AML samples analyzed displayed numerical and structural centrosome aberrations (36.0% ± 16.6%) as compared with peripheral blood mononuclear cells from 21 healthy volunteers (5.2% ± 2.0%; P < .0001). In comparison to AML samples with normal chromosome count, the extent of numerical and structural centrosome aberrations was higher in samples with numerical chromosome changes (50.5% ± 14.2% versus 34.3% ± 12.2%; P < .0001). When the frequency of centrosome aberrations was analyzed within cytogenetically defined risk groups, we found a correlation of the extent of centrosome abnormalities to all 3 risk groups (P = .0015), defined as favorable (22.5% ± 7.3%), intermediate (35.3% ± 13.1%), and adverse (50.3% ± 15.6%). These results indicate that centrosome defects may contribute to the acquisition of chromosome aberrations and thereby to the prognosis in AML.

scholarly journals SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Anna Polak ◽  
Emilia Bialopiotrowicz ◽  
Beata Krzymieniewska ◽  
Jolanta Wozniak ◽  
Marta Stojak ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mitochondrial Biogenesis ◽  
Oxidative Metabolism ◽  
Cell Biology ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Metabolic Reprogramming ◽  
Therapeutic Modality ◽  
Acute Myeloid

Abstract Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38−CD123+ and CD34+CD38−CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials.

scholarly journals Targeting Pharmacokinetic Drug Resistance in Acute Myeloid Leukemia Cells with CDK4/6 Inhibitors

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1596 ◽  
Author(s):  
Ales Sorf ◽  
Simona Sucha ◽  
Anselm Morell ◽  
Eva Novotna ◽  
Frantisek Staud ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
De Novo ◽  
Accumulation Rate ◽  
Inhibitory Effect ◽  
Peripheral Blood Mononuclear ◽  
Drug Biotransformation ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

Pharmacotherapy of acute myeloid leukemia (AML) remains challenging, and the disease has one of the lowest curability rates among hematological malignancies. The therapy outcomes are often compromised by the existence of a resistant AML phenotype associated with overexpression of ABCB1 and ABCG2 transporters. Because AML induction therapy frequently consists of anthracycline-like drugs, their efficiency may also be diminished by drug biotransformation via carbonyl reducing enzymes (CRE). In this study, we investigated the modulatory potential of the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib on AML resistance using peripheral blood mononuclear cells (PBMC) isolated from patients with de novo diagnosed AML. We first confirmed inhibitory effect of the tested drugs on ABCB1 and ABCG2 in ABC transporter-expressing resistant HL-60 cells while also showing the ability to sensitize the cells to cytotoxic drugs even as no effect on AML-relevant CRE isoforms was observed. All tested CDK4/6 inhibitors elevated mitoxantrone accumulations in CD34+ PBMC and enhanced accumulation of mitoxantrone was found with abemaciclib and ribociclib in PBMC of FLT3-ITD- patients. Importantly, the accumulation rate in the presence of CDK4/6 inhibitors positively correlated with ABCB1 expression in CD34+ patients and led to enhanced apoptosis of PBMC in contrast to CD34− samples. In summary, combination therapy involving CDK4/6 inhibitors could favorably target multidrug resistance, especially when personalized based on CD34− and ABCB1-related markers.

scholarly journals Simultaneous Inhibition of Mcl-1 and Induction of DNA Damage Accumulation By Chidamide, a Novel Selective HDACi, Potentiates the Cytotoxicity of ABT-199 in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5767-5767
Author(s):  
Bing Xu ◽  
Kai Chen ◽  
Qianying Yang ◽  
Jie Zha ◽  
Haijun Zhao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Damage Accumulation ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Peripheral Blood Mononuclear ◽  
Normal Peripheral Blood ◽  
Acute Myeloid

Acute myeloid leukemia is a heterogeneous hematopoietic neoplasia with a poor clinical outcome despite its treatment have made great progress in recent years. Strategies for targeting Bcl-2 using ABT-199 attract increasing attentions. however, most treatment failure strongly correlates with acquired up-regulation of MCL-1, which become the Achilles's heel of ABT-199 in clinical use. Here we describe low-cytotoxicity dosage of Chidamide (CS055), a novel selective HDACi designed in China, potentiated the cytotoxicity of ABT-199 towards diverse AML cell lines in vitro and primary samples obtained from patients with AML ex vivo, especially those carrying hyperleukocytosis, as well as highly active in vivo in a AML patient-derived xenograft murine model, while sparing normal peripheral blood mononuclear cells. Mechanistically, ABT-199/CS055-induced cytotoxicity was closely associated with inactivation of Mcl-1 and simultaneous induction of DNA damage accumulation. Of note, we also find a superior resensitization activity of CS055 in contrast with Romidepsin. In summary, our findings suggest that CS055 enhance the eliminating activity of ABT-199 towards AML cells, thus implying a highly promising and potent strategy for treatment of relapsed and refractory AML. Disclosures No relevant conflicts of interest to declare.

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