Histamine H2 Receptor in Blood Cells: A Suitable Target for the Treatment of Acute Myeloid Leukemia

2016 ◽  
pp. 141-160 ◽  
Author(s):  
Federico Monczor ◽  
Sabrina Copsel ◽  
Natalia Fernandez ◽  
Carlos Davio ◽  
Carina Shayo
Keyword(s):  
Acute Myeloid Leukemia ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Histamine H2 Receptor ◽  
H2 Receptor ◽  
Suitable Target ◽  
Acute Myeloid

Enasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia

2019 ◽  
Vol 18 (14) ◽  
pp. 1936-1951 ◽  
Author(s):  
Raghav Dogra ◽  
Rohit Bhatia ◽  
Ravi Shankar ◽  
Parveen Bansal ◽  
Ravindra K. Rawal
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Adverse Effects ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
White Blood Cells ◽  
Phase Iii ◽  
Acute Myeloid

Background: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies. Methods: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes. Result: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc. Conclusion: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.

scholarly journals Chemotherapy-Induced Survivin Regulation in Acute Myeloid Leukemia Cells

2021 ◽  
Vol 11 (1) ◽  
pp. 460
Author(s):  
Petra Otevřelová ◽  
Barbora Brodská
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Survivin Expression ◽  
Mitotic Cell ◽  
Specific Subset ◽  
Suitable Target ◽  
Acute Myeloid Leukemia Cells ◽  
Almost All ◽  
Acute Myeloid

Survivin is a 16.5 kDa protein highly expressed in centrosomes, where it controls proper sister chromatid separation. In addition to its function in mitosis, survivin is also involved in apoptosis. Overexpression of survivin in many cancer types makes it a suitable target for cancer therapy. Western blotting and confocal microscopy were used to characterize the effect of chemotherapy on acute myeloid leukemia (AML) cells. We found enhanced survivin expression in a panel of AML cell lines treated with cytarabine (Ara-C), which is part of a first-line induction regimen for AML therapy. Simultaneously, Ara-C caused growth arrest and depletion of the mitotic cell fraction. Subsequently, the effect of a second component of standard therapy protocol, idarubicin, and of a known survivin inhibitor, YM-155, on cell viability and survivin expression and localization in AML cells was investigated. Idarubicin reversed Ara-C-induced survivin upregulation in the majority of AML cell lines. YM-155 caused survivin deregulation together with a viability decrease in cells resistant to idarubicin treatment, suggesting that YM-155 might be efficient in a specific subset of AML patients. Expression levels of other apoptosis-related proteins, in particular X-linked inhibitor of apoptosis (XIAP), Mcl-1, and p53, and of the cell-cycle inhibitor p21 considerably changed in almost all cases, confirming the off-target effects of YM-155.

Altered Growth Characteristics of Cord Blood Cells after in vivo Exposure to Maternal Acute Myeloid Leukemia and Chemotherapy

2005 ◽  
Vol 114 (2) ◽  
pp. 121-124
Author(s):  
T. Fietz ◽  
R. Arnold ◽  
G. Massenkeil ◽  
K. Rieger ◽  
B. Reufi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cord Blood ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Growth Characteristics ◽  
Cord Blood Cells ◽  
Acute Myeloid

scholarly journals Human-level recognition of blast cells in acute myeloid leukemia with convolutional neural networks

2019 ◽  
Author(s):  
Christian Matek ◽  
Simone Schwarz ◽  
Karsten Spiekermann ◽  
Carsten Marr
Keyword(s):  
Acute Myeloid Leukemia ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
White Blood Cells ◽  
Cell Types ◽  
Hematologic Malignancies ◽  
Malignant Cell ◽  
Morphological Examination ◽  
Blast Cells ◽  
Acute Myeloid

AbstractReliable recognition of malignant white blood cells is a key step in the diagnosis of hematologic malignancies such as Acute Myeloid Leukemia. Microscopic morphological examination of blood cells is usually performed by trained human examiners, making the process tedious, time-consuming and hard to standardise.We compile an annotated image dataset of over 18,000 white blood cells, use it to train a convolutional neural network for leukocyte classification, and evaluate the network’s performance. The network classifies the most important cell types with high accuracy. It also allows us to decide two clinically relevant questions with human-level performance, namely (i) if a given cell has blast character, and (ii) if it belongs to the cell types normally present in non-pathological blood smears.Our approach holds the potential to be used as a classification aid for examining much larger numbers of cells in a smear than can usually be done by a human expert. This will allow clinicians to recognize malignant cell populations with lower prevalence at an earlier stage of the disease.

The Addition of Fludarabine to a Conventional Busulfan/Melphalan/Anti-Thymocyte Globulin (Flu/Bu/Mel/ATG) Preparative Regimen Increased Engraftment without Additional Toxicity.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2944-2944 ◽  
Author(s):  
Sonali Lakshminarayanan ◽  
Adam Mendizabal ◽  
Vinod Prasad ◽  
Suhag Parikh ◽  
Paul Szabolcs ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Cord Blood ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Juvenile Myelomonocytic Leukemia ◽  
Cell Dose ◽  
Preparative Regimen ◽  
Cord Blood Cells ◽  
Acute Myeloid

Abstract Busulfan/Melphalan/ATG (Bu/Mel/ATG) have been used as a preparative regimen in children undergoing hematopoetic stem cell transplantation who are too young for or who cannot tolerate total body irradiation (TBI). While successful in a portion of patients, engraftment rates were lower than those seen in a similar patient population receiving a TBI-containing preparative regimen (Wall et al, Biol Blood Marrow Transplant.2005; 11: 637–646). We hypothesized that the addition of fludarabine, a known immunosuppressive agent used in reduced intensity transplants, to this regimen would increase engraftment without additive toxicity. Fourteen pediatric patients with hematological malignancies (acute myeloid leukemia in remission (n=5); acute myeloid leukemia in relapse (n=3), acute lymphoblastic leukemia, infant type in second remission, n=2; juvenile myelomonocytic leukemia, n=1; myelodysplastic syndrome, n=1; biphenotypic leukemia, in first remission, n=1) and non-malignant conditions (infantile myelofibrosis, n=1) were prepared with intravenous fludarabine 25mg/m2 daily × 5days from day-13 to -9, intravenous targeted busulfan 1mg/kg daily × 4 days from day-8 to -5, intravenous melphalan 45mg/m2 daily × 3 days from day-4 to -2 and intravenous equine anti-thymocyte globulin 30mg/kg daily × 3 days from day-3 to -1. Thirteen patients received unrelated donor cord blood cells and one patient received matched related marrow cells. There were 8 male, 8 Caucasian and 4 CMV seropositive patients. The median age was 1.9 years (range 7 months to 21 years). The median pre-cryopreserved total nucleated cell dose per kg for the unrelated cord blood transplant patients was 11.5 × 107/kg (range, 3.4–32.5) while the median post-thaw total nucleated cell dose per kg was 7.3 × 107/kg (range, 2.5–27.6). The median infused CD34 cells/kg was 0.2 × 105/kg (range, 0.1–0.5) and the median CD3 cells/kg was 19.6 × 106 × kg (range, 6.9–31.0). Nine patients received 4/6 HLA-matched cord blood cells, 3 received 5/6 and 2 patients received 6/6 matched grafts. The addition of fludarabine did not increase or result in any unexpected toxicity. The cumulative incidence (CINC) and median time to neutrophil and platelet engraftment, acute graft versus host disease and overall survival are shown in the table below. These data were compared to a previous published study. Engraftment of neutrophils was superior in the fludarabine/Busulfan/Melphalan/ATG group. Overall survival also improved. While these data of patients are small, these results suggest that the addition of fludarabine to a Busulfan/Melphalan/ATG regimen is safe and may facilitate engraftment with improved survival. Comparison of outcome between Bu/Mel/ATG and Flu/Bu/Mel/ATG CINC of neutrophil engraftment at day 42 CINC of platelet engraftment 50K at day 100 CINC of GrII-IV aGVHD at 100days Overall survival at 12 months Relapse-free survival at 12 months Bu/Mel/ATG 59% (95%CI,44%–78%) 40% (95%CI,31%–69%) 41% (95%CI,25%–56%) 47% (95%CI,30%–64%) 34.4% (95%CI,18.8%–50.6%) Flu/Bu/Mel/ATG 71.4% (95%CI,46%–96.8%) 41.5% (95%CI,10.6%–72.5%) 42.9% (95%CI,29%–56.7%) 55% (95%CI, 24.6%–85.1%) 43.9% (95%CI,13%–74.8%)

MiR-132 and MiR-212 as Regulators of WT1 and GATA2 in Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1283-1283 ◽  
Author(s):  
Maaike Luesink ◽  
Jeannet Nigten ◽  
Ruth H.J.N. Knops ◽  
Theo J.M. de Witte ◽  
Bert A. van der Reijden ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Transcription Factors ◽  
Quantitative Pcr ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Granulocytic Differentiation ◽  
Aberrant Expression ◽  
Differentiation Induction ◽  
Acute Myeloid

Abstract Abstract 1283 Poster Board I-305 Wilms' tumor 1 (WT1) and GATA binding protein 2 (GATA2) transcription factors are highly expressed in hematopoietic stem cells and progenitors. Differentiation of precursor blood cells towards mature blood cells is accompanied by rapid downregulation of both transcription factors. Overexpression of WT1 has been observed in the majority of acute myeloid leukemia (AML) cases. Furthermore, in 10-15% of the AML cases mutations in the WT1 gene occur, which have been correlated with poor prognosis. Aberrant expression of GATA2 in AML has been described as well, but no mutations in this gene have been reported in AML so far. How the (aberrant) expression of WT1 and GATA2 is controlled is not completely clear. A regulatory role for microRNAs (miRNAs) has been described for several transcription factors which regulate hematopoiesis. MiRNAs negatively regulate gene expression by translational repression or degradation of target messenger RNAs (mRNAs). In the present study we investigated the interplay between miRNAs and transcription factors that are involved in myeloid development and malignant transformation towards AML. We studied the expression of 158 miRNAs in the APL cell line NB4 during induction of granulocytic differentiation with all-trans retinoic acid (ATRA). Quantitative PCR specific for mature miRNAs was performed (Applied Biosystems). Twenty out of 158 miRNAs were more than 10-fold upregulated upon differentiation induction with ATRA. MiR-132 and miR212, which are derived from the same pri-miRNA transcript, were most strongly upregulated during ATRA-induced granulocytic differentiation (1200- and 350-fold respectively at 96 hours after ATRA-stimulation). In vitro ATRA-induction of primary APL cells also resulted in upregulation of miR-132 and miR-212. Computational target prediction algorithms were used to identify transcription factors which may be targeted by miR-132 and miR-212. Subsequently, the expression pattern of the predicted targets was determined experimentally in NB4 cells before and after differentiation induction with ATRA using microarray-based mRNA profiling (Affymetrix). In addition, further verification of target gene expression during ATRA-induced differentiation was performed using quantitative PCR. The transcription factors WT1 and GATA2 were predicted as targets of miR-132 and miR-212 by two out of four different prediction programs that were used. Both transcription factors contained putative binding sites for miR-132 and miR-212 in their 3'UTR. When tested on microarray and by quantitative PCR, the expression of WT1 and GATA2 was indeed strongly downregulated during ATRA-induced granulocytic differentiation of NB4 cells (65- and 165-fold respectively at 96 hours after ATRA stimulation) as well as in primary leukemia cells derived from APL patients (30- and 10-fold respectively at 48 hours after ATRA-stimulation). During ATRA-induced differentiation the expression levels of WT1 were positively correlated with the expression levels of GATA2. In addition, WT1 expression was also strongly correlated with GATA2 expression in a cohort of 27 pre-treatment AML cases as well as in 7 healthy controls, suggesting that these genes might be co-regulated to a large extent. To directly prove that WT1 and GATA2 are indeed targeted by miR-132 and miR-212, we are currently performing lentiviral-based overexpression studies of both miRNAs to determine the effect on endogenous WT1 and GATA2 mRNA expression. MicroRNAs which target WT1 and GATA2 may be valuable tools in controlling the aberrant expression of WT1 and GATA2 observed in AML. Disclosures No relevant conflicts of interest to declare.

A Novel Non-Genetic Photostable Approach to Labelling Acute Myeloid Leukemia and Bone Marrow Cells with Quantum Dots

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4818-4818
Author(s):  
Yanwen Zheng ◽  
Zhengwei Mao ◽  
Bin Yin
Keyword(s):  
Bone Marrow ◽  
Quantum Dots ◽  
Acute Myeloid Leukemia ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Hematopoietic Cells ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Dependent Manner ◽  
Acute Myeloid

Abstract Abstract 4818 Acute myeloid leukemia (AML) is a detrimental disease with difficult diagnosis and treatment. Understanding the biology of AML at the molecular and cellular levels would be essential to successful management of the disease. However, the notoriously known difficulty in manipulation of leukemia cells has long hindered the dissection of AML pathogenesis. The advent of CdSe/ZnS quantum dots (QDs) represents an important advancement in the research field of nanotechnology, which have recently also been applied for imaging of live cells. Here, we have introduced a non-genetic approach of marking blood cells, by taking advantage of QD technology. We compared QDs complexed with different vehicles, including a peptide Tat (QDs-Tat), cationic polymer Turbofect (QDs-Tf) and liposome Lipofectamine 2000 (QDs-Lip), in their abilities to mark cells. QDs-Tat showed the highest efficiency in delivery into hematopoietic cells, among the three vehicles. We then examined QDs-Tat labelling of leukemia cell lines, and found that QDs-Tat could label 293T, bone marrow (BM) cells, THP-1, MEG-01 and HL-60 with a decreasing efficiency. The efficiency of QDs-Tat delivery was dependent on the concentration of QDs-Tat applied, but not the length of incubation time. In addition, more uniform intracellular distributions of QDs in 293T and leukemia cells were obtained with QDs-Tat, compared with the granule-like formation obtained with QDs-Lip. Clearly, QD fluorescence was sharp and tolerant to repetitive photo excitations, and could be detected in 293T for up to one week following labelling. In summary, our results suggest that QDs have provided a photostable, non-genetic and transient approach that labels normal and malignant hematopoietic cells in a cell type-, vehicle-, and QD concentration-dependent manner. We expect for potentially wide applications of QDs as an easy and fast tool assisting investigations of various types of blood cells in the near future. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Classification of acute myeloid leukemia subtypes M1, M2 and M3 using active contour without edge segmentation and momentum backpropagation artificial neural network

2018 ◽  
Vol 154 ◽  
pp. 01041 ◽  
Author(s):  
Agus Harjoko ◽  
Tri Ratnaningsih ◽  
Esti Suryani ◽  
Wiharto ◽  
Sarngadi Palgunadi ◽  
...  
Keyword(s):  
Neural Network ◽  
Artificial Neural Network ◽  
Acute Myeloid Leukemia ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Active Contour ◽  
White Blood Cells ◽  
Artificial Neural ◽  
Backpropagation Artificial Neural Network ◽  
Acute Myeloid

Acute Myeloid Leukemia (AML) is a type of cancer which attacks white blood cells from myeloid. AML has eight subtypes, namely: M0, M1, M2, M3, M4, M5, M6, and M7. AML subtypes M1, M2 and M3 are affected by the same type of cells, myeloblast, making it needs more detailed analysis to distinguish. To overcome these obstacles, this research is applying digital image processing with Active Contour Without Edge (ACWE) and Momentum Backpropagation artificial neural network for AML subtypes M1, M2 and M3 classification based on the type of the cell. Six features required as training parameters from every cell obtained by using feature extraction. The features are: cell area, perimeter, circularity, nucleus ratio, mean and standard deviation. The results show that ACWE can be used for segmenting white blood cells with 83.789% success percentage of 876 total cell objects. The whole AML slides had been identified according to the cell types predicted number through training with momentum backpropagation. Five times testing calibration with the best parameter generated averages value of 84.754% precision, 75.887% sensitivity, 95.090% specificity and 93.569% accuracy.

scholarly journals A Comparative Study of Digital Image Segmentation Algorithms for Acute Myeloid Leukemia M1 White Blood Cells Images

2021 ◽  
Vol 4 (2) ◽  
pp. 101
Author(s):  
Nurcahya Pradana Taufik Prakisya ◽  
Andika Setiawan
Keyword(s):  
Acute Myeloid Leukemia ◽  
Image Segmentation ◽  
Digital Image ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Active Contour ◽  
White Blood Cells ◽  
Seed Region ◽  
Segmentation Algorithms ◽  
Acute Myeloid

Various types of algorithms have been widely used for image segmentation in digital image processing. Every algorithm has features that make it unique to be applied to specific cases. One of the applications of image segmentation is to detect white blood cells. Certain objects such as blood cells must be able to be well segmented because their existence is very crucial to support the accuracy of disease detection related to haematology or the branch of medical science that studies the morphology of blood and blood-forming tissues. Three image segmentation algorithms were compared through this study: Seed Region Growing, Otsu Thresholding and Active Contour Without Edge. Comparative analysis of the three algorithms was done by counting the number of white blood cell objects that were successfully segmented with the actual number of cells that were counted manually. A total of 30 images of blood smears were taken from people suffering from acute myeloid leukemia M1. The average accuracy values from each algorithm were used to determine which image segmentation algorithm is the most suitable for application in the case of white blood cells segmentation. The results showed that Active Contour Without Edge is the most appropriate among the other algorithms

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