scholarly journals Common Genetic Aberrations Associated with Metabolic Interferences in Human Type-2 Diabetes and Acute Myeloid Leukemia: A Bioinformatics Approach

2021 ◽  
Vol 22 (17) ◽  
pp. 9322
Author(s):  
Theodora-Christina Kyriakou ◽  
Panagiotis Papageorgis ◽  
Maria-Ioanna Christodoulou
Keyword(s):  
Type 2 Diabetes ◽  
Acute Myeloid Leukemia ◽  
Whole Blood ◽  
Myeloid Leukemia ◽  
Expression Patterns ◽  
Cellular Processes ◽  
Increased Risk ◽  
Transcriptomic Changes ◽  
Acute Myeloid

Type-2 diabetes mellitus (T2D) is a chronic metabolic disorder, associated with an increased risk of developing solid tumors and hematological malignancies, including acute myeloid leukemia (AML). However, the genetic background underlying this predisposition remains elusive. We herein aimed at the exploration of the genetic variants, related transcriptomic changes and disturbances in metabolic pathways shared by T2D and AML, utilizing bioinformatics tools and repositories, as well as publicly available clinical datasets. Our approach revealed that rs11709077 and rs1801282, on PPARG, rs11108094 on USP44, rs6685701 on RPS6KA1 and rs7929543 on AC118942.1 comprise common SNPs susceptible to the two diseases and, together with 64 other co-inherited proxy SNPs, may affect the expression patterns of metabolic genes, such as USP44, METAP2, PPARG, TIMP4 and RPS6KA1, in adipose tissue, skeletal muscle, liver, pancreas and whole blood. Most importantly, a set of 86 AML/T2D common susceptibility genes was found to be significantly associated with metabolic cellular processes, including purine, pyrimidine, and choline metabolism, as well as insulin, AMPK, mTOR and PI3K signaling. Moreover, it was revealed that the whole blood of AML patients exhibits deregulated expression of certain T2D-related genes. Our findings support the existence of common metabolic perturbations in AML and T2D that may account for the increased risk for AML in T2D patients. Future studies may focus on the elucidation of these pathogenetic mechanisms in AML/T2D patients, as well as on the assessment of certain susceptibility variants and genes as potential biomarkers for AML development in the setting of T2D. Detection of shared therapeutic molecular targets may enforce the need for repurposing metabolic drugs in the therapeutic management of AML.

scholarly journals CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia

Blood ◽  
2013 ◽  
Vol 122 (7) ◽  
pp. 1316-1324 ◽  
Author(s):  
Margaret L. Green ◽  
Wendy M. Leisenring ◽  
Hu Xie ◽  
Roland B. Walter ◽  
Marco Mielcarek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Early Relapse ◽  
Relapse Risk ◽  
Allogeneic Hct ◽  
Increased Risk ◽  
Key Points ◽  
Cmv Reactivation ◽  
Reduced Risk ◽  
Acute Myeloid

Key Points CMV reactivation after HCT is associated with a reduced risk of early relapse in patients with AML but not other disease groups. The benefit, however, is offset by an increased risk of nonrelapse mortality.

Genomics of Acute Myeloid Leukemia Diagnosis and Pathways

2017 ◽  
Vol 35 (9) ◽  
pp. 934-946 ◽  
Author(s):  
Lars Bullinger ◽  
Konstanze Döhner ◽  
Hartmut Döhner
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Clinical Care ◽  
Clonal Expansion ◽  
Disease Classification ◽  
Disease Evolution ◽  
Myeloid Neoplasms ◽  
Increased Risk ◽  
Acute Myeloid

In recent years, our understanding of the molecular pathogenesis of myeloid neoplasms, including acute myeloid leukemia (AML), has been greatly advanced by genomics discovery studies that use novel high-throughput sequencing techniques. AML, similar to most other cancers, is characterized by multiple somatically acquired mutations that affect genes of different functional categories, a complex clonal architecture, and disease evolution over time. Patterns of mutations seem to follow specific and temporally ordered trajectories. Mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1, and IDH2, are commonly acquired early and are present in the founding clone. The same genes are frequently found to be mutated in elderly individuals along with clonal expansion of hematopoiesis that confers an increased risk for the development of hematologic cancers. Furthermore, such mutations may persist after therapy, lead to clonal expansion during hematologic remission, and eventually lead to relapsed disease. In contrast, mutations involving NPM1 or signaling molecules (eg, FLT3, RAS) typically are secondary events that occur later during leukemogenesis. Genetic data are now being used to inform disease classification, risk stratification, and clinical care of patients. Two new provisional entities, AML with mutated RUNX1 and AML with BCR- ABL1, have been included in the current update of the WHO classification of myeloid neoplasms and AML, and mutations in three genes— RUNX1, ASXL1, and TP53—have been added in the risk stratification of the 2017 European LeukemiaNet recommendations for AML. Integrated evaluation of baseline genetics and assessment of minimal residual disease are expected to further improve risk stratification and selection of postremission therapy. Finally, the identification of disease alleles will guide the development and use of novel molecularly targeted therapies.

microRNAs in acute myeloid leukemia: Expression patterns, correlations with genetic and clinical parameters, and prognostic significance

2009 ◽  
pp. n/a-n/a ◽  
Author(s):  
Rotraud Wieser ◽  
Marcel Scheideler ◽  
Hubert Hackl ◽  
Maria Engelmann ◽  
Christine Schneckenleithner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Expression Patterns ◽  
Prognostic Significance ◽  
Clinical Parameters ◽  
Acute Myeloid

scholarly journals The possible significance of trisomy 8 in acute myeloid leukemia

2017 ◽  
Vol 5 (6) ◽  
pp. 2652 ◽  
Author(s):  
Salil N. Vaniawala ◽  
Monika V. Patel ◽  
Pratik D. Chavda ◽  
Shivangi H. Zaveri ◽  
Pankaj K. Gadhia
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chromosomal Aberrations ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Prognostic Significance ◽  
Chromosomal Translocation ◽  
Banding Technique ◽  
Trisomy 8 ◽  
Increased Risk ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is a heterogeneous disorder that results from a block in the differentiation of haematopoietic progenitor cells along with uncontrolled proliferation. Trisomy 8 is the most common recurring numerical chromosomal aberrations in acute myeloid leukemia (AML). It occurs either as a sole anomaly or together with other additional chromosomal aberrations. The prognostic significance of trisomy 8 in presence of other additional chromosomal abnormality depends on clonal cytogenetic changes. The patients with trisomy 8 had shorter survival with significantly increased risk with other chromosomal abnormality.Methods: Total 139 patients were screened between January 2016 to November 2016 who were suspected of AML cases. Bone marrow cultures were set up using conventional cytogenetic methods. Chromosomal preparation was made and subjected to GTG banding technique. Banded metaphases were analysed and karyotyped for further analysis.Results: Cytogenetic evaluation of karyotyped of 139 suspected AML patients showed 52 with t(8;21)(q22;q22), 36 with t(15;17)(q22;q12), and 11 with inv(16)(p13;q22). The rest 40 cases found with additional chromosomal abnormalities, of which 16 were sole trisomy 8 and 24 cases were found with other chromosomal abnormalities In addition, only one person found with t(8;21) and trisomy 8, while  three person having t(15;17) with trisomy 8.Conclusions: AML is considered to be one of the most important cytogenetic prognostic determinants. Recurrent chromosomal translocation with trisomy 8 varying 1.9% for t(8;21) and 8.3% for t(15;17). In the present study trisomy 8 in AML with known favourable anomalies is very small. Therefore, it cannot be taken as a prognostic marker.

scholarly journals Combined inhibition of JAK/STAT pathway and lysine-specific demethylase 1 as a therapeutic strategy in CSF3R/CEBPA mutant acute myeloid leukemia

2020 ◽  
Vol 117 (24) ◽  
pp. 13670-13679 ◽  
Author(s):  
Theodore P. Braun ◽  
Cody Coblentz ◽  
Brittany M. Smith ◽  
Daniel J. Coleman ◽  
Zachary Schonrock ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Therapeutic Strategy ◽  
Hematologic Malignancy ◽  
Therapeutic Interventions ◽  
Leukemia Cells ◽  
Lysine Specific Demethylase ◽  
Increased Risk ◽  
Stat Signaling ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a deadly hematologic malignancy with poor prognosis, particularly in the elderly. Even among individuals with favorable-risk disease, approximately half will relapse with conventional therapy. In this clinical circumstance, the determinants of relapse are unclear, and there are no therapeutic interventions that can prevent recurrent disease. Mutations in the transcription factor CEBPA are associated with favorable risk in AML. However, mutations in the growth factor receptor CSF3R are commonly co-occurrent in CEBPA mutant AML and are associated with an increased risk of relapse. To develop therapeutic strategies for this disease subset, we performed medium-throughput drug screening on CEBPA/CSF3R mutant leukemia cells and identified sensitivity to inhibitors of lysine-specific demethylase 1 (LSD1). Treatment of CSF3R/CEBPA mutant leukemia cells with LSD1 inhibitors reactivates differentiation-associated enhancers driving immunophenotypic and morphologic differentiation. LSD1 inhibition is ineffective as monotherapy but demonstrates synergy with inhibitors of JAK/STAT signaling, doubling median survival in vivo. These results demonstrate that combined inhibition of JAK/STAT signaling and LSD1 is a promising therapeutic strategy for CEBPA/CSF3R mutant AML.

scholarly journals Differential expression of miRNAs in acute myeloid leukemia quantified by Nextgen sequencing of whole blood samples

PLoS ONE ◽  
2019 ◽  
Vol 14 (3) ◽  
pp. e0213078 ◽  
Author(s):  
Aakriti Pandita ◽  
Poornima Ramadas ◽  
Aarati Poudel ◽  
Nibal Saad ◽  
Ankit Anand ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Differential Expression ◽  
Whole Blood ◽  
Myeloid Leukemia ◽  
Blood Samples ◽  
Nextgen Sequencing ◽  
Whole Blood Samples ◽  
Acute Myeloid

scholarly journals Long-term risk for subsequent leukemia after treatment for childhood cancer: a report from the Childhood Cancer Survivor Study

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6315-6318 ◽  
Author(s):  
Kerri Nottage ◽  
Jennifer Lanctot ◽  
Zhenghong Li ◽  
Joseph P. Neglia ◽  
Smita Bhatia ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Childhood Cancer ◽  
Cancer Survivor ◽  
Myeloid Leukemia ◽  
Childhood Cancer Survivor ◽  
Primary Therapy ◽  
Increased Risk ◽  
Childhood Cancer Survivor Study ◽  
Acute Myeloid

Abstract Previous investigations of cancer survivors report that the cumulative incidence of subsequent leukemia plateaus between 10 and 15 years after primary therapy. Risk beyond 15 years has not been comprehensively assessed, primarily because of lack of long-term follow-up. Among 5-year survivors from the Childhood Cancer Survivor Study cohort, 13 pathologically confirmed cases of subsequent leukemia occurred ≥ 15 years after primary malignancy, with a mean latency of 21.6 years (range, 15-32 years). Seven were acute myeloid leukemia (2 acute promyelocytic leukemia with t(15;17), 2 with confirmed preceding myelodysplastic syndrome), 4 acute lymphoblastic leukemia (2 pre-B lineage, 1 T cell, 1 unknown), and 2 other. Two acute myeloid leukemia cases had the 7q− deletion. The standardized incidence ratio was 3.5 (95% confidence interval, 1.9-6.0). Median survival from diagnosis of subsequent leukemia was 2 years. This is the first description of a statistically significant increased risk of subsequent leukemia ≥ 15 years from primary diagnosis of childhood cancer.

scholarly journals Predicting Complete Remission of Acute Myeloid Leukemia: Machine Learning Applied to Gene Expression

2019 ◽  
Vol 18 ◽  
pp. 117693511983554 ◽  
Author(s):  
Ophir Gal ◽  
Noam Auslander ◽  
Yu Fan ◽  
Daoud Meerzaman
Keyword(s):  
Gene Expression ◽  
Machine Learning ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Statistical Significance ◽  
Expression Patterns ◽  
Pathway Enrichment Analysis ◽  
Data Set ◽  
Acute Myeloid

Machine learning (ML) is a useful tool for advancing our understanding of the patterns and significance of biomedical data. Given the growing trend on the application of ML techniques in precision medicine, here we present an ML technique which predicts the likelihood of complete remission (CR) in patients diagnosed with acute myeloid leukemia (AML). In this study, we explored the question of whether ML algorithms designed to analyze gene-expression patterns obtained through RNA sequencing (RNA-seq) can be used to accurately predict the likelihood of CR in pediatric AML patients who have received induction therapy. We employed tests of statistical significance to determine which genes were differentially expressed in the samples derived from patients who achieved CR after 2 courses of treatment and the samples taken from patients who did not benefit. We tuned classifier hyperparameters to optimize performance and used multiple methods to guide our feature selection as well as our assessment of algorithm performance. To identify the model which performed best within the context of this study, we plotted receiver operating characteristic (ROC) curves. Using the top 75 genes from the k-nearest neighbors algorithm (K-NN) model ( K = 27) yielded the best area-under-the-curve (AUC) score that we obtained: 0.84. When we finally tested the previously unseen test data set, the top 50 genes yielded the best AUC = 0.81. Pathway enrichment analysis for these 50 genes showed that the guanosine diphosphate fucose (GDP-fucose) biosynthesis pathway is the most significant with an adjusted P value = .0092, which may suggest the vital role of N-glycosylation in AML.

Preemptive Tecovirimat Use in an Active Duty Service Member Who Presented With Acute Myeloid Leukemia After Smallpox Vaccination

2019 ◽  
Vol 69 (12) ◽  
pp. 2205-2207 ◽  
Author(s):  
David A Lindholm ◽  
Raymond D Fisher ◽  
Jay R Montgomery ◽  
Whitni Davidson ◽  
Patricia A Yu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Leukemia ◽  
Treatment Strategy ◽  
Myeloid Leukemia ◽  
Adverse Reactions ◽  
Active Duty ◽  
Service Member ◽  
Smallpox Vaccination ◽  
Increased Risk ◽  
Acute Myeloid

Abstract Smallpox vaccine is contraindicated in immunosuppression due to increased risk for adverse reactions (eg, progressive vaccinia). We describe the first-ever use of tecovirimat as a preemptive vaccinia virus treatment strategy during induction chemotherapy in an active duty service member who presented with acute leukemia and inadvertent autoinoculation after smallpox vaccination.

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