508 research outputs found
The clinical and biological consequences of different FLT3 mutations in patients with AML
No full textCharacterisation of pathogenic markers in acute myeloid leukaemia (AML) may benefit
patients through refinement of risk stratification, application of molecularly targeted
therapy and improved understanding of AML biology. Whilst the presence of an
internal tandem duplication (ITD) within the fms-like tyrosine kinase-3 (FLT3) gene is
known to predict adverse outcome in young adults with AML, the clinical significance
of activating mutations in the tyrosine kinase domain (TKD) of FLT3 is unclear.
Therefore, a highly sensitive and specific denaturing-HPLC technique was developed to
screen for FLT3/TKDs in 1339 young adult patients with AML. Mutations were
detected in 161 (12%) cases, with a high incidence in patients with inv(16) (24%;
P=.009), a group in which FLT3/ITDs are uncommon. Unlike FLT3/ITDs, FLT3/TKDs
were associated with a favourable long-term outcome with a 10-year overall survival
(OS) of 36% for FLT3 WT, 51% for FLT3/ITD-TKD+ and 24% for FLT3/ITD+TKDpatients
(P<.001). The relative FLT3/TKD mutant level was highly variable with the
favourable prognosis residing in those patients with greater than 25% mutant alleles
(10-year OS of 59%), possibly reflecting the stage at which the mutation is acquired.
The mechanism of FLT3 activation also influenced sensitivity to FLT3-inhibitor
induced cytotoxicity, with FLT3/ITD+ blast cells more sensitive than FLT3/TKD+ cells.
Following lentiviral transduction, FLT3/ITD-transduced 32Dcl3 and Ba/F3 cells
demonstrated more rapid proliferation than FLT3/TKD-transduced cells. In an NB4 cell
line model of ATRA-induced myeloid differentiation, the presence of a FLT3/ITD
inhibited differentiation unlike a FLT3/TKD mutation which increased differentiation.
Furthermore, FLT3/ITD-transduced CD34 positive haematopoietic stem cells showed
greater cytokine-free survival of colony forming cells than FLT3/TKD-transduced cells.
Signalling studies also revealed that a FLT3/ITD induced stronger STAT5 activation
than a FLT3/TKD mutation. This unexpected genotype-phenotype relationship is of
direct relevance to current clinical decision making in AML, and may also provide
insights into mechanisms of chemoresistance
A Crowdsourcing Approach to Developing and Assessing Prediction Algorithms for AML Prognosis
No full textabstract: Acute Myeloid Leukemia (AML) is a fatal hematological cancer. The genetic abnormalities underlying AML are extremely heterogeneous among patients, making prognosis and treatment selection very difficult. While clinical proteomics data has the potential to improve prognosis accuracy, thus far, the quantitative means to do so have yet to be developed. Here we report the results and insights gained from the DREAM 9 Acute Myeloid Prediction Outcome Prediction Challenge (AML-OPC), a crowdsourcing effort designed to promote the development of quantitative methods for AML prognosis prediction. We identify the most accurate and robust models in predicting patient response to therapy, remission duration, and overall survival. We further investigate patient response to therapy, a clinically actionable prediction, and find that patients that are classified as resistant to therapy are harder to predict than responsive patients across the 31 models submitted to the challenge. The top two performing models, which held a high sensitivity to these patients, substantially utilized the proteomics data to make predictions. Using these models, we also identify which signaling proteins were useful in predicting patient therapeutic response.The article is published at http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.100489
Impacts of the 5th AML Directive on the Provision of Investment Services in Czech Republic
No full textThis contribution deals with the impact of the Vth AML directive, which updated Directive (EU) 2015/849 of the European Parliament and of the Council of 20 May 2015 on the prevention of the use of the financial system for the purposes of money laundering or terrorist financing, on the provision of the investment services in Czech Republic. The main aim of the contribution is to confirm or disprove the hypothesis that the Vth AML Directive significantly affected the activities of investment service providers. The author used scientific methods, especially induction and deduction, to confirm or disprove the above hypothesis. The paper also discusses the future regulation of the anti-money laundering area.
A transcriptomic based deconvolution framework for assessing differentiation stages and drug responses of AML
No full textThe diagnostic spectrum for AML patients is increasingly based on genetic abnormalities due to their prognostic and predictive value. However, information on the AML blast phenotype regarding their maturational arrest has started to regain importance due to its predictive power for drug responses. Here, we deconvolute 1350 bulk RNA-seq samples from five independent AML cohorts on a single-cell healthy BM reference and demonstrate that the morphological differentiation stages (FAB) could be faithfully reconstituted using estimated cell compositions (ECCs). Moreover, we show that the ECCs reliably predict ex-vivo drug resistances as demonstrated for Venetoclax, a BCL-2 inhibitor, resistance specifically in AML with CD14+ monocyte phenotype. We validate these predictions using LUMC proteomics data by showing that BCL-2 protein abundance is split into two distinct clusters for NPM1-mutated AML at the extremes of CD14+ monocyte percentages, which could be crucial for the Venetoclax dosing patients. Our results suggest that Venetoclax resistance predictions can also be extended to AML without recurrent genetic abnormalities and possibly to MDS-related and secondary AML. Lastly, we show that CD14+ monocytic dominated Ven/Aza treated patients have significantly lower overall survival. Collectively, we propose a framework for allowing a joint mutation and maturation stage modeling that could be used as a blueprint for testing sensitivity for new agents across the various subtypes of AML.Pattern Recognition and Bioinformatic
I. A SHORT HISTORY OF CURRENCY AND MONEY LAUNDERING CONTROLS IN
No full textOffice of Technical Assistance have assisted in preparing this paper. The views expressed in this paper are solely those of the author and do not necessarily reflect the views and policies of ADB or its Board of Governors or the governments they represent. ADB does not guarantee the accuracy of the data included in this publication and accepts no responsibility for any consequence of their use. Use of the term “country ” does not imply any judgment by the author or ADB as to the legal or other status of any territorial entity. This report is dedicated to the staff of the Anti-Money Laundering Council (AMLC) of the Philippines, AML/CFT related government agencies, and the private sector partners who are working hard to design a well regulated market place that includes AML/CFT and fraud safeguards. Special thanks to Globe and SMART Telecom, the Philippine regulatory community and the AMLC, all of whom were generous with their time and advice. We hope this paper stimulates our counterparts worldwide to examine the issues arising from these new integrated financial and telecommunications (wireless) systems as they relate to AML/CFT operations and the security of financial systems. 1 This paper is an excerpt from a larger work to be published by John Forbes with the assistance of Valeria J
Leveraging ADL Archetypes by transforming them to AML Archetypes
No full textUniversity of Minnesota M.S. thesis. August 2015. Major: Biomedical Informatics and Computational Biology. Advisors: Christopher Chute, Claudia Neuhauser. 1 computer file (PDF); ix, 37 pages.The Clinical Information Modeling Initiative (CIMI) has developed the Archetype Modeling Language (AML) specifications, which is now an Object Management Group (OMG) standard. The AML is for modeling archetypes using the Unified Modeling Language (UML). The development of the AML specifications is part of one of the goals for CIMI - to deliver a shared repository of clinical models that is open and free to use. The AML is an attractive option to create, reuse and extend archetypes and the ability to share these archetypes greatly improves interoperability. AML is new standard with lot of promises and benefits, but lacks support of any tooling to get started with creating AML archetypes easily. The ADL archetypes are built using a proprietary format and hence lack an easy gateway to Model-Driven Architecture. The author has created maps for transforming existing archetypes in the OpenEHR's Archetype Definition Language (ADL) to AML workspace. These proven mappings bridge the gap between ADL and AML by providing seamless transition and leverage the ADL archetypes to the AML modeling workspace. This thesis is about these mappings and their implementation.Sharma, Deepak. (2015). Leveraging ADL Archetypes by transforming them to AML Archetypes. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/174713
An agonist antibody prefers relapsed AML for induction of cells that kill each other
No full textPreviously, we reported an agonist antibody to a cytokine receptor, Thrombopoietin receptor (TPOR) that effectively induces cytotoxic killer cells from precursor tumor cells isolated from newly diagnosed AML patients. Here, we show that the TPOR agonist antibody can induce even relapsed AML cells into killer cells more potently than newly diagnosed AML cells. After stimulation by the agonist antibody, these relapsed leukemic cells enter into a differentiation process of killer cells. The antibody-induced killer cells express, Granzyme B and Perforin that assault and kill other members of the AML cell population. Particularly, the agonist antibody showed potent efficacy on the AML xenograft model in mice using the NOD/LtSz-scid IL2Rγc null (NSG) mice. These results show that the TPOR agonist antibody that induces AML cells to kill each other is effective on both relapsed AML cells and in vivo. Therefore, this study suggests a new strategy for the treatment of cancer relapse after chemotherapy. © 2019, The Author(s).TRU
Characterisation of T cell defects in acute myeloid leukaemia
No full textPhDUnderstanding the immune system in patients with cancer and how it interacts with malignant cells is critical for the development of successful immunotherapeutic strategies at a time when novel cancer treatment approaches are required. Acute myeloid leukaemia (AML) results in widespread interaction between the malignant cells and T cells and as such, offers an opportunity to study these interactions. A flow cytometric analysis of T cells in the peripheral blood of patients presenting with AML illustrated that the absolute number of T cells is increased in AML compared with healthy controls. Furthermore, a large population of CD3+56+ cells was identified. These cells are not natural killer T cells but effector T cells that may represent a failing immunosurveillance mechanism. Two technical issues were explored: how to separate T cells from the peripheral blood of newly diagnosed AML patients and the impact of the method of immunomagnetic cell separation on the gene expression profile of healthy T cells. Gene expression profiling was subsequently performed on T cells from AML patients compared with healthy controls. Global differences in transcription were observed suggesting aberrant T cell activation patterns in AML. As differentially regulated genes involved in actin cytoskeletal formation were noted, a functional assessment of the ability of T cells from AML patients to form immunological synapses was performed. This illustrated that although T cells from AML patients can form conjugates with autologous blasts, their ability to form immune synapses and recruit phosphotyrosine signalling molecules to that signalling interface is impaired. Taken together, these findings demonstrate that numerically T cells are plentiful in AML however they are abnormal in terms of the genes they are transcribing and in their interactions with tumour cells. Targeting immunological synapse formation may represent an important means of improving T cell recognition of tumour cells across a range of cancers
Comparison of outcomes of HCT in blast phase of BCR-ABL1- MPN with de novo AML and with AML following MDS
No full textFull author list omitted for brevity. For the full list of authors, see article.Comparative outcomes of allogeneic hematopoietic cell transplantation (HCT) for BCR-ABL1- myeloproliferative neoplasms (MPNs) in blast phase (MPN-BP) vs de novo acute myeloid leukemia (AML), and AML with prior myelodysplastic syndromes (MDSs; post-MDS AML), are unknown. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared HCT outcomes in 177 MPN-BP patients with 4749 patients with de novo AML, and 1104 patients with post-MDS AML, using multivariate regression analysis in 2 separate comparisons. In a multivariate Cox model, no difference in overall survival (OS) or relapse was observed in patients with MPN-BP vs de novo AML with active leukemia at HCT. Patients with MPN-BP in remission had inferior OS in comparison with de novo AML in remission (hazard ratio [HR], 1.40 [95% confidence interval [CI], 1.12-1.76]) due to higher relapse rate (HR, 2.18 [95% CI, 1.69-2.80]). MPN-BP patients had inferior OS (HR, 1.19 [95% CI, 1.00-1.43]) and increased relapse (HR, 1.60 [95% CI, 1.31-1.96]) compared with post-MDS AML. Poor-risk cytogenetics were associated with increased relapse in both comparisons. Peripheral blood grafts were associated with decreased relapse in MPN-BP and post-MDS AML (HR, 0.70 [95% CI, 0.57-0.86]). Nonrelapse mortality (NRM) was similar between MPN-BP vs de novo AML, and MPN-BP vs post-MDS AML. Total-body irradiation-based myeloablative conditioning was associated with higher NRM in both comparisons. Survival of MPN-BP after HCT is inferior to de novo AML in remission and post-MDS AML due to increased relapse. Relapse-prevention strategies are required to optimize HCT outcomes in MPN-BP
Targeted Knockdown of MYC in AML Cells Using G-quadruplex Interacting Small Molecules
No full textabstract: Acute Myeloid Leukemia (AML) is a disease that occurs when genomic changes alter expression of key genes in myeloid blood cells. These changes cause them to resume an undifferentiated state, proliferate, and maintain growth throughout the body. AML is commonly treated with chemotherapy, but recent efforts to reduce therapy toxicity have focused on drugs that specifically target and inhibit protein products of the cancer’s aberrantly expressed genes. This method has proved difficult for some proteins because of structural challenges or mutations that confer resistance to therapy. One potential method of targeted therapy that circumvents these issues is the use of small molecules that stabilize DNA secondary structures called G-quadruplexes. G-quadruplexes are present in the promoter region of many potential oncogenes and have regulatory roles in their transcription. This study analyzes the therapeutic potential of the compound GQC-05 in AML. This compound was shown in vitro to bind and stabilize the regulatory G-quadruplex in the MYC oncogene, which is commonly misregulated in AML. Through qPCR and western blot analysis, a GQC-05 mediated downregulation of MYC mRNA and protein was observed in AML cell lines with high MYC expression. In addition, GQC-05 is able to reduce cell viability through induction of apoptosis in sensitive AML cell lines. Concurrent treatment of AML cell lines with GQC-05 and the MYC inhibitor (+)JQ1 showed an antagonistic effect, indicating potential competition in the silencing of MYC. However, GQC-05 is not able to reduce MYC expression significantly enough to induce apoptosis in less sensitive AML cell lines. This resistance may be due to the cells’ lack of dependence on other potential GQC-05 targets that may help upregulate MYC or stabilize its protein product. Three such genes identified by RNA-seq analysis of GQC-05 treated cells are NOTCH1, PIM1, and RHOU. These results indicate that the use of small molecules to target the MYC promoter G-quadruplex is a viable potential therapy for AML. They also support a novel mechanism for targeting other potentially key genetic drivers in AML and lay the groundwork for advances in treatment of other cancers driven by G-quadruplex regulated oncogenes.Dissertation/ThesisMasters Thesis Molecular and Cellular Biology 201
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