• Molecules and Cells
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• v.46 no.10
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• pp.611-626
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• 2023

Acute myeloid leukemia (AML) is a heterogeneous disease caused by distinctive mutations in individual patients; therefore, each patient may display different cell-type compositions. Although most patients with AML achieve complete remission (CR) through intensive chemotherapy, the likelihood of relapse remains high. Several studies have attempted to characterize the genetic and cellular heterogeneity of AML; however, our understanding of the cellular heterogeneity of AML remains limited. In this study, we performed single-cell RNA sequencing (scRNAseq) of bone marrow-derived mononuclear cells obtained from same patients at different AML stages (diagnosis, CR, and relapse). We found that hematopoietic stem cells (HSCs) at diagnosis were abnormal compared to normal HSCs. By improving the detection of the DNMT3A R882 mutation with targeted scRNAseq, we identified that DNMT3A-mutant cells that mainly remained were granulocyte-monocyte progenitors (GMPs) or lymphoid-primed multipotential progenitors (LMPPs) from CR to relapse and that DNMT3A-mutant cells have gene signatures related to AML and leukemic cells. Copy number variation analysis at the single-cell level indicated that the cell type that possesses DNMT3A mutations is an important factor in AML relapse and that GMP and LMPP cells can affect relapse in patients with AML. This study advances our understanding of the role of DNMT3A in AML relapse and our approach can be applied to predict treatment outcomes.

• BMB Reports
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• v.51 no.9
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• pp.444-449
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• 2018

Acute myeloid leukemia (AML) is one of the most common hematological malignancies all around the world. MicroRNAs have been determined to contribute various cancers initiation and progression, including AML. Although microRNA-204 (miR-204) exerts anti-tumor effects in several kinds of cancers, its function in AML remains unknown. In the present study, we assessed miR-204 expression in AML blood samples and cell lines. We also investigated the effects of miR-204 on cellular function of AML cells and the underlying mechanisms of the action of miR-204. Our results showed that miR-204 expression was significantly downregulated in AML tissues and cell lines. In addition, overexpression of miR-204 induced growth inhibition and apoptosis in AML cells, including AML5, HL-60, Kasumi-1 and U937 cells. Cell cycle analysis further confirmed an augmentation in theapoptotic subG1 population by miR-204 overexpression. Mechanistically, baculoviral inhibition of apoptosis protein repeat containing 6 (BIRC6) was identified as a direct target of miR-204. Enforcing miR-204 expression increased the luciferase activity and expression of BIRC6, as well as p53 and Bax expression. Moreover, restoration of BIRC6 reversed the pro-apoptotic effects of miR-204 overexpression in AML cells. Taken together, this study demonstrates that miR-204 causes AML cell apoptosis by targeting BIRC6, suggesting miR-204 may play an anti-carcinogenic role in AML and function as a novel biomarker and therapeutic target for the treatment of this disease.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.1547-1551
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• 2016

Background: Acute myeloid leukemia (AML) is a clonal hematopoietic disorder resulting from genetic alterations in normal hematopoietic stem cells. The aim of this study was to evaluate prognostic factors and survival of AML patients in the Northeast of Iran. Materials and Methods: This retrospective study covered 96 patients with AML referred to Emam Reza Hospital, Mashhad city, Iran, from 2009 to 2015. Age, sex, blood group, type of AML, fever, consumption of amphotericin B, cytogenetic forms and survival were analyzed. Also, WBC, hemoglobin and platelet levels were checked. Mean follow-up was 30.5 months (60.4% mortality). Survival was plotted by GraphPad Prism 5 with Log-rank test. Results: The mean age for all AML patients at diagnosis was 40.4 years (range, 17-77 years). Some 42.7% patients were aged <35 years and 40.6% were male. In all patients, 76% had fever and 50% consumed amphotericin. T(15;17)(q22;q21) had the most prevalence (37.7%) compared to other forms. Out of 92 patients, O+(30.4%) was the most common blood group and AML-M5 (28.3%) the most common subtype. There was a significant difference in survival based on WBC and consumption of amphotericin B (P<0.05). Conclusions: WBC level, fever and consumption of amphotericin B proved to be factors for survival of AML patients. The mean age for patients in Iran is lower than other areas in the World and also survival in this study was higher than in other studies.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.9
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• pp.4395-4399
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• 2016

The FLT3-ITD mutation is one of the most frequent genetic abnormalities in acute myeloid leukemia (AML) where it is associated with a poor prognosis. The FLT3-ITD mutation could, therefore, be a potential molecular prognostic marker important for risk-stratified treatment options. We amplified the FLT3 gene at exon 14 and 15 in 52 AML patients (aged between 2 months and 74 years) from 4 referral centers (a university hospital and 3 regional hospitals in Northeast Thailand), using a simple PCR method. FLT3-ITD mutations were found in 10 patients (19.2%), being more common in adults than in children (21.1% vs. 14.3%) and more prevalent in patients with acute promyelocytic leukemia (AML-M3) than AML-non M3 (4 of 10 AML-M3 vs. 6 of 42 AML-non M3 patients). Duplication sequences varied in size-between 27 and 171 nucleotides (median=63.5) and in their location. FLT3-ITD mutations with common duplication sequences accounted for a significant percentage in AML patients in northeastern Thailand. This simple PCR method is feasible for routine laboratory practice and these data could help tailor use of the national protocol for AML.

• Korean Journal of Radiology
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• v.22 no.5
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• pp.735-741
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• 2021

Objective: To evaluate circularity as a quantitative shape factor of small renal tumor on computed tomography (CT) in differentiating fat-poor angiomyolipoma (AML) from renal cell carcinoma (RCC). Materials and Methods: In 257 consecutive patients, 257 pathologically confirmed renal tumors (either AML or RCC less than 4 cm), which did not include visible fat on unenhanced CT, were retrospectively evaluated. A radiologist drew the tumor margin to measure the perimeter and area in all the contrast-enhanced axial CT images. In each image, a quantitative shape factor, circularity, was calculated using the following equation: 4 x π x (area ÷ perimeter²). The median circularity (circularity index) was adopted as a representative value in each tumor. The circularity index was compared between fat-poor AML and RCC, and the receiver operating characteristic (ROC) curve analysis was performed. Univariable and multivariable binary logistic regression analysis was performed to determine the independent predictor of fat-poor AML. Results: Of the 257 tumors, 26 were AMLs and 231 were RCCs (184 clear cell RCCs, 25 papillary RCCs, and 22 chromophobe RCCs). The mean circularity index of AML was significantly lower than that of RCC (0.86 ± 0.04 vs. 0.93 ± 0.02, p < 0.001). The mean circularity index was not different between the subtypes of RCCs (0.93 ± 0.02, 0.92 ± 0.02, and 0.92 ± 0.02 for clear cell, papillary, and chromophobe RCCs, respectively, p = 0.210). The area under the ROC curve of circularity index was 0.924 for differentiating fat-poor AML from RCC. The sensitivity and specificity were 88.5% and 90.9%, respectively (cut-off, 0.90). Lower circularity index (≤ 0.9) was an independent predictor (odds ratio, 41.0; p < 0.001) for predicting fat-poor AML on multivariable logistic regression analysis. Conclusion: Circularity is a useful quantitative shape factor of small renal tumor for differentiating fat-poor AML from RCC.

• Biomedical Science Letters
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• v.23 no.1
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• pp.1-7
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• 2017

It is known that acute myeloid leukemia (AML) is a heterogeneous blood cancer, which is enormously propagated by self-renewing leukemia stem cells (LSCs). The persistence of LSCs after chemotherapy can contribute to minimal residual disease and relapse by LSCs can be evoked promptly. Elucidating special molecules and cellular activity of LSCs is an extremely important to eliminate AML. Despite an increasing understanding of the origin of LSCs by incessant study, AML still remains a notorious disease with high mortality. An exact identification of the LSCs that sustain the proliferation of neoplastic clone is a fundamental issue in AML treatment. CD34+CD38- conventional phenotype is overall regarded as LSCs, but it has a limitation that is still hard to demarcate exactly due to similarity with normal hematopoietic stem cells (HSCs). Not all primary blasts and progenitors have equal function, thus a bona fide marker for identifying LSCs from HSCs is needed in hematologic malignancy, especially in AML. These findings have direct important implications in both in mechanistic study of LSCs as well as in the strategies of more effective therapies. In this review, I briefly summarized current advances in LSCs biology, focusing on membrane markers and a functional behavior of LSCs in AML treatment with monoclonal antibodies. Ultimately, it may be helpful in overviewing the status of LSC research, while expecting the clinic benefits of target therapy by specific inhibition.

• Journal of the Korean Society of Radiology
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• v.84 no.2
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• pp.454-459
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• 2023

Hematologic malignancy of the breast is very rare. Here, we report a case of relapsed acute myeloid leukemia (AML) presenting as multiple breast masses. A 77-year-old female visited an outpatient clinic reporting palpable masses in both breasts. She had a medical history of AML, which showed complete remission after nine cycles of chemotherapy. On mammography and ultrasonography, there were multiple masses correlated with her palpable symptoms accompanied by enlarged lymph nodes. Core needle biopsy immunohistochemistry (IHC) results indicated AML and blastic plasmacytoid dendritic cell neoplasm. AML was confirmed using bone marrow biopsy. Although very rare, when a patient with a history of hematologic malignancy presents a palpable mass in the breast, clinicians should conduct proper tissue analysis, including IHC stating for leukemic markers, to guide appropriate diagnosis and treatment.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.1519-1529
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• 2016

Background: Matrix metalloproteinase -2 (gelatinase-A, Mr 72,000 type IV collagenase, MMP-2) and -9 (gelatinase-B, Mr 92,000 type IV collagenase, MMP-9) are key molecules that play roles in tumor growth, invasion, tissue remodeling, metastasis and stem-cell regulation by digesting extracellular matrix barriers. MMP-2 and -9 are well known to impact on solid cancer susceptibility, whereas, in hematological malignancies, a paucity of data is available to resolve the function of these regulatory molecules in bone marrow mononuclear cells (BM-MNCs) and stromal cells of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Objectives: The present study aimed to investigate mRNA expression and gelatinase A and B secretion from BM-MNCs in vitro and genotypic associations of MMP-2 (-1306 C/T; rs243865), MMP-9 (-1562 C/T; rs3918242), tissue inhibitor of metalloproteinase -1 (TIMP-1) (372T/C; rs4898, Exon 5) and TIMP-2 (-418G/C; rs8179090) in MDS and AML. Results: The study covered cases of confirmed MDS (n=50), AML (n=32) and healthy controls (n=110). MMP-9 mRNA expression revealed 2 fold increased expression in MDS-RAEB II and 2.5 fold in AML M-4 (60-70% blasts). Secretion of gelatinase-B also revealed the MMP-9 mRNA expression and ELISA data also supported these data. We noted that those patients having more blast crises presented with more secretion of MMP-9 and its mRNA expression. In contrast MMP-9 (-1562 C/T) showed significant polymorphic associations in MDS (p<0.02) and AML (p<0.02). MMP-9 mRNA expression of C/T and T/T genotypes were 1.5 and 2.5 fold increased in MDS and AML respectively. In AML, MMP-2 C/T and T/T genotypes showed 2.0 fold mRNA expression. Only MMP-9 (-1306 C/T) showed significant 4 fold (p<0.001) increased risk with chemical and x-ray exposed MDS, while tobacco and cigarette smokers have 3 fold (p<0.04) risk in AML. Conclusions: In view of our results, MMP-9 revealed synergistic secretion and expression in blast crises of MDS and AML with 'gene' polymorphic effects and is significantly associated with increased risk with tobacco, cigarette and environmental exposure. Release and secretion of these enzymes may influence hematopoietic cell behavior and may be important in the clinical point of view. It may offer valuable tools for diagnosis and prognosis, as well as possible targets for the treatments.

• Journal of Life Science
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• v.28 no.5
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• pp.540-546
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• 2018

Annona muricata, generally known as soursop, graviola, or sirsak, is native to the warmest tropical areas of North and South America and is now widely distributed throughout tropical and subtropical parts of the world, including India and Nigeria. This study tested the contents of polyphenolic compounds, flavonoids, and minerals, as well as the antioxidative effects of DPPH radical-scavenging activity, Fe/Cu-reducing power, linoleic-acid peroxidation using thiobarbituric-acid (TBA) methods and peroxidation of rat-hepatocyte microsomes, and ${\beta}$-carotene bleaching assay. These were tested with in-vitro experimental models using water, ethanol, and methanol extracts of the Annona muricata leaf (AMl). Water extracts of AMl showed the highest extraction yield (1.76%). The total polyphenol-compound concentration was the highest in the methanol extract of AMl. However, the flavonoids concentration was the highest in the ethanol extracts of AMl. AMlMl major minerals were Ca, K, and Mg. In DPPH radical-scavenging activity, the contents exhibited a strong scavenging effect on the ethanol and methanol extracts of AMl. Additionally, the Fe/Cu-reducing power was strong in ethanol and methanol extracts of AMl. $Fe^{2+}$/ascorbate-induced linoleic-acid peroxidation using TBA methods and auto-oxidation of rat-hepatic microsomes showed strong antioxidative activities in ethanol extracts of AMl. ${\beta}$-Carotene bleaching was also highest in the ethanol extracts of AMl. These results may provide the basic data to understand the chemical characteristics and antioxidative effects of Annona muricata leaf extract for the development of functional foods.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4215-4220
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• 2012

AML (Acute myeloid leukemia) is a form of blood cancer where growth of myeloid cells occurs in the bone marrow. The prognosis is poor in general for many reasons. One is the presence of leukaemia-specific recognition markers such as FLT3 (fms-like tyrosine kinase 3). Another name of FLT3 is stem cell tyrosine kinase-1 (STK1), which is known to take part in proliferation, differentiation and apoptosis of hematopoietic cells, usually being present on haemopoietic progenitor cells in the bone marrow. FLT3 act as an independent prognostic factor for AML. Although a vast literature is available about the association of FLT3 with AML there still is a need of a brief up to date overview which draw a clear picture about this association and their effect on overall survival.