Detection Of Acute Myeloid Leukemia Research Articles

MicroRNA mediated gene regulatory circuits leads to machine learning based preliminary detection of acute myeloid leukemia

Acute Myeloid Leukemia (AML) can be detected based on morphology, cytochemistry, immunological markers, and cytogenetics. MicroRNAs (miRNAs) influence key biological pathways in multiple haematological malignancies including AML. In this work, we have analysed the miRNome and the transcriptome of normal and AML samples and have identified the significant set of miRNA-target mRNA pairs present within AML- Peripheral Blood and AML- Bone Marrow samples from both tissue and cell lines. The miRNA target genes are further filtered based on their functional significance in AML system. These filtered genes constitute the set of selected miRNA target features, which have been finally used for developing machine learning based prediction tool, ‘TbAMLPred’ for preliminary detection of AML.This model implements both unsupervised clustering and supervised classification algorithms that would increase the reliability of prediction. Our results show that the selected miRNA target-based features can separate the control and disease samples linearly. Overall, we put forward ‘TbAMLPred’ for a non-invasive mode of preliminary AML diagnosis in future.Github link for accessing TbAMLPred: https://github.com/zglabDIB/TbAMLPred

Relapsed acute myeloid leukemia presenting as conjunctival myeloid sarcoma: a case report

BackgroundConjunctival myeloid sarcoma (MS) as an isolated presentation of acute myeloid leukemia (AML) relapse is rare. Here, we report a case of unilateral conjunctival MS revealed as a sign of AML relapse.Case presentationA 50-year-old man with a history of AML in remission visited our clinic presenting with a left conjunctival injection persisting for 1 month. Diffuse subconjunctival thickening with conjunctival vascular engorgement was observed. Ultrasound biomicroscopy revealed a hyper-reflective, thickened conjunctiva in his left eye. During the incisional biopsy, the lesion was strongly attached to the underlying sclera; histopathologic examination revealed infiltration of leukemic blasts. The relapse of AML was confirmed by a successive bone marrow biopsy. The ocular lesion disappeared after allogeneic peripheral blood stem cell transplantation (PBSCT) and concomitant salvage radiotherapy on the left eye. The patient has remained in remission for 3 years after allogeneic PBSCT.ConclusionsIncidental conjunctival lesions can indicate AML relapse in patients treated earlier for AML. An ophthalmologist may have a role in the early detection of AML when a patient presents with an atypical conjunctival lesion.

A lightweight deep learning system for automatic detection of blood cancer

Microscopic analysis of blood-cells is an essential and vital task for the early diagnosis of life-threatening hematological disorders like blood cancer (leukemia). We have presented an effective and computationally efficient approach for automatically detecting and classifying Acute Lymphoblastic Leukemia (ALL) and Acute Myeloid Leukemia (AML). Currently, transfer learning has succeeded as a preferred approach in medical image analysis since it achieves excellent performance in a small database. This paper proposes a lightweight transfer-learning-based feature extraction followed by Support Vector Machine (SVM)-based classification technique for efficient ALL and AML detection. It yields a faster and more efficient system due to the depth-wise separable convolution, tunable multiplier, and inverted residual bottleneck structure. Moreover, the SVM-based classification improves the overall performance by optimizing the hyperplane location. Furthermore, the experimental results signify that our proposed system gains superior performance than others in all these three publicly available standard ALLIDB1, ALLIDB2, and ASH databases.

An increase in DNA G-quadruplex formation in acute myelocytic leukemia is detected by a supramolecular probe

Acute myeloid leukemia (AML) is a common acute leukemia in both adults and children, with poor early detection and diagnosis. Therefore, identifying new indicators for AML detection is significant for effective treatment. Here, we developed a supramolecular probe that exhibits high specificity and sensitivity to G-quadruplex structures in physiological buffer solution, chromosomes, and cells. Using this probe, we tested the DNA extracted from different types of cells and found that the DNA extracted from human acute myeloid leukemia cells HL-60 and KG-1 enhanced the probe fluorescence more significantly than the DNA extracted from other cells. This phenomenon may be related to a large number of G-quadruplexes in acute myeloid leukemia cells, implicating that G-quadruplex levels may be a potential indicator for the detection of acute myeloid leukemia.

Detection of Acute Myeloid Leukemia based on White Blood Cell Morphological Imaging using Naïve Bayesian Algorithm

The process of diagnosing AML is based on the complete blood-count analysis of the patients. As such, it involves high energy consumption, long completion times, and is rather expensive compared to conventional medical practices. One of the methods for identifying tumor cells involves the utilization of image-processing techniques based on the morphology of white blood cells (WBCs). The principal objective of this study involves the identification of AML cells—especially of the AML M1 and AML M2 types—through morphological imaging of WBCs using the Naïve Bayes' Classifier. The Image-processing methods used in this study include YCbCr color space classification, image thresholding, morphological operations, chain code representation, and the use of bounding boxes. Regardless of the processing technique used, all identification procedures, performed in this study, were based on the Naïve Bayes' Classifier. The test process was performed on 30 images of each of the AML M1 and M2 cell types. The use of the cell identification method proposed in this study demonstrated an accuracy of 73.33%. While the accuracy of cell type identification is 54.92%. Based on the results obtained in this study, it is inferred that the Naïve Bayes' Classifier method can be employed in the process of identifying dominant AML cell types amongst AML M1 and AML M2 (myeloblast, promyelocyte, myelocyte, and metamyelocyte) based on the morphology of WBCs.

DCE-MRI for Detection of Acute Myeloid Leukemia Derived Bone Marrow Vascular Dysfunction

Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults. While the clinical presentation is quite uniform, it is a highly heterogeneous disease at the genetic level. Using intravital two-photon microscopy in AML xenograft models, we have previously showed that AML patient-derived samples induced a common pathologic bone marrow (BM) vascular phenotype. To understand the translational potential of our findings we have optimized dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for the assessment of BM vascular dysfunction. We quantified non-model based parameters from DCE-MRI scans: Contrast Enhancement (CE); Wash-in Rate (WiR); and Wash-out Rate (WoR). CE reflects tissue vascular density and is a measurement of the proportion of fully functional vessels per pixel area, WIR reflects blood flow and tissue perfusion, and WoR reflects vascular permeability and tissue clearance capacity. We first measured DCE parameters in control mice. We observed no gender-related differences in BM DCE parameters, while we found significant age-related changes. As mice age, BM vascular density decreases together with increased vascular permeability and reduced tissue clearance capacity. When compared to age- matched controls, mice injected with AML cell lines showed decreased vascular density, decreased blood inflow, increased vascular permeability and reduced tissue clearance capacity. There was a progressive decline in BM vascular function as the disease burden increased, particularly in WiR and WoR parameters, with even low levels of leukemia significantly altering BM vascular function. When analyzing mice injected with AML patient samples, changes in BM vascular function were more dependent on the AML sample than on the engraftment. Low disease burden did not significantly change DCE vascular parameters. At high disease burden, patient-derived xenografts show different degrees of vascular disruption, spanning from global altered DCE parameters to milder phenotypes. Upon AraC treatment, altered vascular parameters remained unchanged in most of the cases, suggesting inability to fully rescue BM vascular function. In conclusion, we showed that DCE-MRI is able to detect consistent changes associated with BM vasculature induced by aging and leukemia. Despite the heterogeneous nature of the disease, our method captures different degrees of vascular alterations, with WIR having the highest diagnostic potential. Our results further suggest that the detection of a pathologic vascular phenotype in the BM of AML patients could be of use in the clinical scenario. Disclosures No relevant conflicts of interest to declare.

A Cascade Targeted and Activatable NIR-II Nanoprobe for Highly Sensitive Detection of Acute Myeloid Leukemia in an Orthotopic Model

Acute myeloid leukemia (AML) remains a significant concern in modern medicine. Early diagnosis is the key to improving the therapeutic effects of AML. In the present work, a cascade-targeted and ac...

SERS assessment of the cancer-specific methylation pattern of genomic DNA: towards the detection of acute myeloid leukemia in patients undergoing hematopoietic stem cell transplantation.

In this label-free surface-enhanced Raman scattering (SERS) study of genomic DNA, we demonstrate that the cancer-specific DNA methylation pattern translates into specific spectral differences. Thus, DNA extracted from an acute myeloid leukemia (AML) cell line presented a decreased intensity of the 1005 cm-1 band of 5-methylcytosine compared to normal DNA, in line with the well-described hypomethylation of cancer DNA. The unique methylation pattern of cancer DNA also influences the DNA adsorption geometry, resulting in higher adenine SERS intensities for cancer DNA. The possibility of detecting cancer DNA based on its SERS spectrum was validated on peripheral blood genomic DNA samples from n = 17 AML patients and n = 17 control samples, yielding an overall classification of 82% based on the 1005 cm-1 band of 5-methylcytosine. By demonstrating the potential of SERS in assessing the methylation status in the case of real-life DNA samples, the study paves the way for novel methods of diagnosing cancer. Graphical abstract.

Identification of novel serum biomarker for the detection of acute myeloid leukemia based on liquid chromatography-mass spectrometry

Acute myeloid leukemia (AML) is a life-threatening hematological malignancy. Traditional diagnosis of AML depends on invasive bone marrow biopsies. To recognize the metabolic characteristics related with AML and search for early non-invasive biomarkers of AML, in this work we applied ultra-high performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOFMS)-based metabolomoc method to profile serum metabolites from 55 de novo AML patients and 45 age- and gender-matched healthy subjects and to screen and validate AML biomarkers. We observed AML-related metabolic differences mainly involved in alanine, aspartate and glutamate metabolism; d-Glutamine and d-glutamate metabolism; tryptophan metabolism; taurine and hypotaurine metabolism; and phenylalanine metabolism as well as fatty acid metabolism. A serum metabolite biomarker panel consisting of glutamic acid, kynurenine and oleic acid was defined and validated based on binary logistic regression analysis and receiver operating characteristic curves (ROC) analysis, yielding an area under the ROC curve (AUC) of 0.981 with 0.975 sensitivity and 0.933 specificity in the discovery set and an AUC of 0.973 with 0.933 sensitivity and 0.933 specificity in the validation set. This work demonstrated the UHPLC- MS-based metabolomics as a low invasive potential tool for the detection of AML, and this composite serum metabolite panel exhibited good diagnostic performance for AML in this case-control study and deserved further validation in a large-scale clinical trial. The identified metabolic pathways were also potentially worthy of further studying the pathogenesis of AML.

Circulating miR-92a, miR-143 and miR-342 in Plasma are Novel Potential Biomarkers for Acute Myeloid Leukemia.

MicroRNAs (miRNAs) are small non-coding RNAs that function as post-transcriptional gene expression regulators. The expression profiling of miRNAs has already entered into cancer clinics as diagnostic and prognostic biomarkers to assess tumor initiation, progression and response to treatment in cancer patients. Recent studies have opened the way for the use of circulating miRNAs as non-invasive diagnosis and prognosis of Acute myeloid leukemia (AML). The aim of this study was to identify plasma miR-92a, miR-143 and miR-342 expression signatures in AML patients to introduce new markers for establishing AML diagnosis and prognosis. Blood samples were collected from 65 AML patients and 50 controls. The expression of three target miRNAs (miR-92a, miR-143 and miR-342) was measured using quantitative real-time PCR method. Plasma levels of miR-92a, miR-143 and miR-342 were significantly lower in AML patients in comparison with control group. Receiver operator characteristic (ROC) analysis revealed that the sensitivity and specificity values of miR-92a were 81.5% and 94%, respectively, with a cut-off value of 0.704. The sensitivity and specificity values of miR-143 were 87.7% and 80%, respectively, with a cut-off value of 0.65. The sensitivity and specificity values of miR-342 were 75.4% and 90%, respectively, with a cut-off value of 0.479. Our findings suggest that plasma miR-92a, miR-143 and miR-342 could be promising novel circulating biomarkers in clinical detection of AML.

Chimeric Antigen Receptor-Modified T Cells for the Treatment of Acute Myeloid Leukemia Expressing CD33

Relapsed acute myeloid leukemia (AML) is an aggressive disease with very poor outcomes. Redirection of T-cell specificity via chimeric antigen receptor (CAR) has shown promising anti-tumor activity in clinical trials, particularly for B cell linage malignancies. CD33 is a transmembrane protein expressed on normal and malignant myeloid-derived cells as well (as on subsets of activated T cells and NK cells). Since this protein is commonly expressed on AML cells, we sought to evaluate the efficacy of targeting AML with CD33-specific CAR-T cells. We generated a lentiviral construct to co-express CD33-specific CAR and a kill switch based on a tag derived from the epidermal growth factor receptor. The latter allows for the conditional elimination of CAR-T cells in vivo. Following transduction of primary T cells, we confirmed CAR and kill switch co-expression by flow cytometry and western blot analyses. Elimination of genetically modified T cells was demonstrated using the clinically-available antibody, cetuximab. CD33 CAR-T cells demonstrated specific cytotoxicity to CD33+ target cell lines. CD33 CAR-T cells were also activated to produce IFNg, TNF, and IL-2 cytokines in response to CD33+ target cells. Furthermore, adoptive transfer of CD33 CAR-T in immunocompromised (NSG) mice bearing established CD33+(CD19neg) AML (MOLM-13) tumor resulted in reduction of tumor burden and improvement of overall survival, compared to control mice receiving CD19 CAR-T cells or no immunotherapy (Figure). Sampling of blood demonstrated the persistence of the CD33 CAR-T cells with no detection of AML (MOLM-13) tumor cells. These pre-clinical data demonstrate the effectiveness of CD33 CAR-T cells in targeting CD33+ AML tumor cells and provide a rationale for future clinical evaluation in AML patients with unmet medical need. [Display omitted] DisclosuresSong:Intrexon Corporation: Employment, Equity Ownership. Swartz:Intrexon Corporation: Employment, Equity Ownership. Biesecker:Intrexon Corporation: Employment, Equity Ownership. Borda:Intrexon Corporation: Employment. Shah:Intrexon Corporation: Employment, Equity Ownership. Wierda:Genentech: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Acerta: Research Funding. Cooper:MD Anderson Cancer Center: Employment; Intrexon: Equity Ownership; Sangamo BioSciences: Patents & Royalties; Targazyme,Inc.,: Equity Ownership; City of Hope: Patents & Royalties; ZIOPHARM Oncology: Employment, Equity Ownership, Patents & Royalties; Miltenyi Biotec: Honoraria; Immatics: Equity Ownership. Chan:Intrexon Corporation: Employment, Equity Ownership.

Nucleophosmin Immunohistochemistry in Residual Disease Detection of Acute Myeloid Leukemia

Nucleophosmin (NPM1) is a nuclear protein that is mutated and localized in cytoplasm in approximately 30% of acute myeloid leukemia (AML) and 50% to 60% of cytogenetically normal AML. The goal of the study is to evaluate whether subcellular localization of NPM1 by IHC is stable in AML patients and whether detection of NPMc+ by IHC is useful …

Monoclonal Antibodies against Nucleophosmin Mutants: Potentials for the Detection of Acute Myeloid Leukemia

Nucleophosmin (NPM1) gene mutations resulting in cytoplasmic delocalization of Nucleophosmin (NPMc+) are the most common genetic alteration in acute myeloid leukemia (AML). Here, we attempted to prepare monoclonal antibodies (mAbs) against NPM1 mutation A (NPM-mA) and investigated the mAbs' clinical utility in immunohistochemical detection of NPMc+AML. The pET-32a-NPM-mA vector with the whole open reading frame of the NPM-mA gene was constructed. E.coli BL21 transformed with the vector were induced to express the NPM-mA recombinant protein. BALB/c mice were immunized with the recombinant NPM-mA. Positive clones were selected by indirect ELISA and the mAbs were obtained. Immunohistochemistry was performed to detect the NPMc+ in bone marrow smears from 10 AML patients with NPM-mA. The results showed that the pET-32a-NPM-mA vector was successfully constructed and the NPM-mA recombinant protein was used to immunize the mice. Two positive clones (2G3 and 3F9) were selected. The mAbs against NPM-mA were raised, but did cross-react with wild type NPM1. The mAbs can be used to detect the cytoplasmic dislocation of NPM1 in all AMLs carrying NPM-mA. Our results show that anti-NPM-mA mAbs were produced. Though they would cross-react with wild type NPM1, the mAbs may still have potential in the detection of NPMc+AMLs.