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Discovery of human cell selective effector molecules using single cell multiplexed activity metabolomics.
Earl DC, Ferrell PB, Leelatian N, Froese JT, Reisman BJ, Irish JM, Bachmann BO
(2018) Nat Commun 9: 39
MeSH Terms: Aged, Bone Marrow, Cell Extracts, Chromatography, Liquid, DNA Damage, Female, Flow Cytometry, Humans, Leukemia, Leukemia, Myeloid, Acute, Lymphocytes, Male, Mass Spectrometry, Metabolome, Metabolomics, Monocytes, Signal Transduction, Streptomyces, Tumor Cells, Cultured, Young Adult
Show Abstract · Added January 4, 2018
Discovering bioactive metabolites within a metabolome is challenging because there is generally little foreknowledge of metabolite molecular and cell-targeting activities. Here, single-cell response profiles and primary human tissue comprise a response platform used to discover novel microbial metabolites with cell-type-selective effector properties in untargeted metabolomic inventories. Metabolites display diverse effector mechanisms, including targeting protein synthesis, cell cycle status, DNA damage repair, necrosis, apoptosis, or phosphoprotein signaling. Arrayed metabolites are tested against acute myeloid leukemia patient bone marrow and molecules that specifically targeted blast cells or nonleukemic immune cell subsets within the same tissue biopsy are revealed. Cell-targeting polyketides are identified in extracts from biosynthetically prolific bacteria, including a previously unreported leukemia blast-targeting anthracycline and a polyene macrolactam that alternates between targeting blasts or nonmalignant cells by way of light-triggered photochemical isomerization. High-resolution cell profiling with mass cytometry confirms response mechanisms and is used to validate initial observations.
3 Communities
1 Members
0 Resources
20 MeSH Terms
High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML.
Zhao Y, Liu Q, Acharya P, Stengel KR, Sheng Q, Zhou X, Kwak H, Fischer MA, Bradner JE, Strickland SA, Mohan SR, Savona MR, Venters BJ, Zhou MM, Lis JT, Hiebert SW
(2016) Cell Rep 16: 2003-16
MeSH Terms: Antineoplastic Agents, Azepines, Cell Line, Tumor, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Clustered Regularly Interspaced Short Palindromic Repeats, DNA-Directed RNA Polymerases, Drug Resistance, Neoplasm, Enhancer Elements, Genetic, Gene Expression Regulation, Leukemic, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myeloid, Acute, MicroRNAs, Multigene Family, Myeloid Cell Leukemia Sequence 1 Protein, Promoter Regions, Genetic, Protein Isoforms, Proteins, Proto-Oncogene Proteins c-kit, Transcription, Genetic, Translocation, Genetic, Triazoles
Show Abstract · Added April 6, 2017
Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3' to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2, that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
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23 MeSH Terms
High-Dimensional Analysis of Acute Myeloid Leukemia Reveals Phenotypic Changes in Persistent Cells during Induction Therapy.
Ferrell PB, Diggins KE, Polikowsky HG, Mohan SR, Seegmiller AC, Irish JM
(2016) PLoS One 11: e0153207
MeSH Terms: Aged, Bone Marrow, Female, Flow Cytometry, Humans, Immunophenotyping, Induction Chemotherapy, Leukemia, Myeloid, Acute, Male, Middle Aged, Phenotype, Pilot Projects, Treatment Outcome, Young Adult
Show Abstract · Added April 14, 2016
The plasticity of AML drives poor clinical outcomes and confounds its longitudinal detection. However, the immediate impact of treatment on the leukemic and non-leukemic cells of the bone marrow and blood remains relatively understudied. Here, we conducted a pilot study of high dimensional longitudinal monitoring of immunophenotype in AML. To characterize changes in cell phenotype before, during, and immediately after induction treatment, we developed a 27-antibody panel for mass cytometry focused on surface diagnostic markers and applied it to 46 samples of blood or bone marrow tissue collected over time from 5 AML patients. Central goals were to determine whether changes in AML phenotype would be captured effectively by cytomic tools and to implement methods for describing the evolving phenotypes of AML cell subsets. Mass cytometry data were analyzed using established computational techniques. Within this pilot study, longitudinal immune monitoring with mass cytometry revealed fundamental changes in leukemia phenotypes that occurred over time during and after induction in the refractory disease setting. Persisting AML blasts became more phenotypically distinct from stem and progenitor cells due to expression of novel marker patterns that differed from pre-treatment AML cells and from all cell types observed in healthy bone marrow. This pilot study of single cell immune monitoring in AML represents a powerful tool for precision characterization and targeting of resistant disease.
4 Communities
2 Members
0 Resources
14 MeSH Terms
Comparison of 60 and 80 mg/m of daunorubicin in induction therapy of acute myeloid leukaemia.
Vaezi M, Bahar B, Mousavi A, Yaghmai M, Kasaeian A, Souri M, Jahani M, Alimoghaddam K, Ghavamzadeh A
(2017) Hematol Oncol 35: 101-105
MeSH Terms: Adolescent, Adult, Antibiotics, Antineoplastic, Chromosome Aberrations, Cytarabine, Daunorubicin, Disease-Free Survival, Dose-Response Relationship, Drug, Drug Administration Schedule, Febrile Neutropenia, Female, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute, Male, Middle Aged, Mycoses, Neutropenia, Prevalence, Prospective Studies, Remission Induction, Treatment Outcome, Young Adult
Show Abstract · Added September 28, 2015
For finding better method of acute myeloid leukaemia (AML) induction, we designed a prospective clinical trial to find a more effective regimen with least toxicity for induction therapy of AML. Hence, we examined different accepted doses of daunorubicin and their outcomes. Total of 114 patients were included in the study. Fifty-five patients received 60 mg/m of daunorubicin (arm 1) 1 h IV infusion for 3 days, and the remaining 59 received 80 mg/m (arm 2) 1 h IV infusion for 3 days. Continuous infusion of 100 mg/m /day of cytosine arabinozide IV for 24 h for 7 days was given in both groups. Complete remission rate was 77.78% in group 1 and 76.92% in group 2 (p = 0.92). One-year overall survival was 55.85% [standard error (SE) = 8.05%] in arm 1 and 57.94% (SE = 7.32%) in arm 2. Median follow-up time was 11.1 (SE = 1.43) and 10.28 (SE = 1.29) months, respectively. One-year disease-free survival was 64.41% (SE = 7.39%) in arm 1 and 54.86% (SE = 7.53%) in arm 2. Complete remission, overall survival and disease-free survival were statistically the same in both groups (p = 0.92, 0.697, 0.31). Toxicity and safety profile were similar in two groups but need to transfusion was higher in arm 2. Febrile neutropenia, days of antibiotics consumption and invasive fungal infection prevalence did not show any difference. Mean transfused packed cells and platelets rate were higher in the group that received higher dose of daunorubicin. Considering these results, we found that 60 mg/m of daunorubicin would be more rational and as effective with lower toxicity to 80 mg/m in induction therapy of AML patients at least as scheduled in our trial. Copyright © 2015 John Wiley & Sons, Ltd.
Copyright © 2015 John Wiley & Sons, Ltd.
0 Communities
1 Members
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24 MeSH Terms
Ethnic variation of TET2 SNP rs2454206 and association with clinical outcome in childhood AML: a report from the Children's Oncology Group.
Kutny MA, Alonzo TA, Gamazon ER, Gerbing RB, Geraghty D, Lange B, Heerema NA, Sung L, Aplenc R, Franklin J, Raimondi SC, Hirsch BA, Konkashbaev A, Cox NJ, Onel K, Gamis AS, Meshinchi S
(2015) Leukemia 29: 2424-6
MeSH Terms: Child, DNA-Binding Proteins, Genotype, Humans, Leukemia, Myeloid, Acute, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins, Quantitative Trait Loci
Added February 22, 2016
0 Communities
2 Members
0 Resources
8 MeSH Terms
Regulation of AKT signaling by Id1 controls t(8;21) leukemia initiation and progression.
Wang L, Man N, Sun XJ, Tan Y, García-Cao M, Cao MG, Liu F, Hatlen M, Xu H, Huang G, Mattlin M, Mehta A, Rampersaud E, Benezra R, Nimer SD
(2015) Blood 126: 640-50
MeSH Terms: Animals, Apoptosis, Carcinogenesis, Cell Line, Tumor, Disease Progression, Gene Knockdown Techniques, Humans, Inhibitor of Differentiation Protein 1, Inhibitor of Differentiation Proteins, Leukemia, Myeloid, Acute, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Protein Interaction Domains and Motifs, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Signal Transduction, Translocation, Genetic
Show Abstract · Added January 27, 2016
Transcriptional regulators are recurrently altered through translocations, deletions, or aberrant expression in acute myeloid leukemia (AML). Although critically important in leukemogenesis, the underlying pathogenetic mechanisms they trigger remain largely unknown. Here, we identified that Id1 (inhibitor of DNA binding 1) plays a pivotal role in acute myeloid leukemogenesis. Using genetically modified mice, we found that loss of Id1 inhibited t(8;21) leukemia initiation and progression in vivo by abrogating protein kinase B (AKT)1 activation, and that Id1 interacted with AKT1 through its C terminus. An Id1 inhibitor impaired the in vitro growth of AML cells and, when combined with an AKT inhibitor, triggered even greater apoptosis and growth inhibition, whereas normal hematopoietic stem/progenitor cells were largely spared. We then performed in vivo experiments and found that the Id1 inhibitor significantly prolonged the survival of t(8;21)(+) leukemic mice, whereas overexpression of activated AKT1 promoted leukemogenesis. Thus, our results establish Id1/Akt1 signaling as a potential therapeutic target in t(8;21) leukemia.
© 2015 by The American Society of Hematology.
0 Communities
1 Members
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19 MeSH Terms
The outcome of allogeneic hematopoietic cell transplantation for children with FMS-like tyrosine kinase 3 internal tandem duplication-positive acute myelogenous leukemia.
Schechter T, Gassas A, Chen H, Pollard J, Meshinchi S, Zaidman I, Hitzler J, Abdelhaleem M, Ho R, Domm J, Woolfrey A, Frangoul H
(2015) Biol Blood Marrow Transplant 21: 172-5
MeSH Terms: Adolescent, Child, Child, Preschool, Chromosome Duplication, Female, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Humans, Immunosuppressive Agents, Leukemia, Myeloid, Acute, Male, Myeloablative Agonists, Recurrence, Retrospective Studies, Siblings, Survival Analysis, Transplantation Conditioning, Transplantation, Homologous, Treatment Outcome, Unrelated Donors, Whole-Body Irradiation, Young Adult, fms-Like Tyrosine Kinase 3
Show Abstract · Added February 25, 2015
FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) is a somatic mutation associated with poor outcome when treated with chemotherapy alone. In children, hematopoietic stem cell transplantation (HSCT) is recommended, but very limited data on outcome are reported. We determined the outcome of 29 children with FLT3/ITD-positive acute myelogenous leukemia (AML) who underwent allogeneic HSCT in 4 pediatric centers. Eleven patients (38%) received matched related donor hematopoietic stem cells and 18 (62%) received alternative donors. Eighteen patients (62%) received total body irradiation (TBI)-based regimens. No patients experienced transplantation-related mortality. Eleven patients (38%) experienced relapsed disease. The cumulative incidence of relapse at 2 years was 34.7% (95% confidence interval [CI], 20.4% to 54.9%). Two-year disease-free survival (DFS) and overall survival (OS) were 65.3% (95% CI, 45.1% to 79.6%) and 82.2% (95% CI, 58.5% to 91.3%), respectively. There was no difference in the DFS of patients who received transplants from related donors versus the DFS of those who received transplants from alternative donors (hazard ratio [HR], 2.64; 95% CI, .79 to 8.76; P = .10), using univariate analysis. Patients with higher FLT3/ITD ratio at diagnosis had significantly worse DFS (HR, 1.42; 95% CI, 1.04 to 1.93; P = .03). The use of TBI in the preparative regimen was associated with superior DFS (HR, .29; 95% CI, .08 to .99; P = .04) and OS (HR, .07; 95% CI, .01 to .62; P = .002). We conclude that allogeneic HSCT improves DFS and OS in children with FLT3/ITD-positive AML compared with what has been reported in those treated with chemotherapy alone.
Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
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23 MeSH Terms
PDGFRB-rearranged T-lymphoblastic leukemia/lymphoma occurring with myeloid neoplasms: the missing link supporting a stem cell origin.
Ondrejka SL, Jegalian AG, Kim AS, Chabot-Richards DS, Giltnane J, Czuchlewski DR, Shetty S, Sekeres MA, Yenamandra A, Head D, Jagasia M, Hsi ED
(2014) Haematologica 99: e148-51
MeSH Terms: Adult, Bone Marrow, Gene Expression, Humans, Karyotype, Leukemia, Myeloid, Male, Middle Aged, Neoplastic Stem Cells, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Receptor, Platelet-Derived Growth Factor beta, Translocation, Genetic
Added January 20, 2015
0 Communities
1 Members
0 Resources
12 MeSH Terms
Molecular pathways: targeting NRAS in melanoma and acute myelogenous leukemia.
Johnson DB, Smalley KS, Sosman JA
(2014) Clin Cancer Res 20: 4186-92
MeSH Terms: Antineoplastic Agents, GTP Phosphohydrolases, Humans, Leukemia, Myeloid, Acute, Melanoma, Membrane Proteins, Molecular Targeted Therapy, Prognosis, Signal Transduction
Show Abstract · Added June 27, 2014
Successful targeting of specific oncogenic "driver" mutations with small-molecule inhibitors has represented a major advance in cancer therapeutics over the past 10 to 15 years. The most common activating oncogene in human malignancy, RAS (rat sarcoma), has proved to be an elusive target. Activating mutations in RAS induce mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase-AKT pathway signaling and drive malignant progression in up to 30% of cancers. Oncogenic NRAS mutations occur in several cancer types, notably melanoma, acute myelogenous leukemia (AML), and less commonly, colon adenocarcinoma, thyroid carcinoma, and other hematologic malignancies. Although NRAS-mutant tumors have been recalcitrant to targeted therapeutic strategies historically, newer agents targeting MAP/ERK kinase 1 (MEK1)/2 have recently shown signs of clinical efficacy as monotherapy. Combination strategies of MEK inhibitors with other targeted agents have strong preclinical support and are being evaluated in clinical trials. This review discusses the recent preclinical and clinical studies about the role of NRAS in cancer, with a focus on melanoma and AML.
©2014 American Association for Cancer Research.
0 Communities
1 Members
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9 MeSH Terms
Cytotoxic T-lymphocyte antigen-4 single nucleotide polymorphisms are not associated with outcomes after unrelated donor transplantation: a center for international blood and marrow transplant research analysis.
Sengsayadeth S, Wang T, Lee SJ, Haagenson MD, Spellman S, Fernandez Viña MA, Muller CR, Verneris MR, Savani BN, Jagasia M
(2014) Biol Blood Marrow Transplant 20: 900-3
MeSH Terms: Adolescent, Adult, Aged, CTLA-4 Antigen, Female, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Myeloid, Acute, Male, Middle Aged, Multivariate Analysis, Myelodysplastic Syndromes, Polymorphism, Single Nucleotide, Treatment Outcome, Unrelated Donors, Young Adult
Show Abstract · Added March 20, 2014
Cytotoxic T-lymphocyte antigen-4 (CTLA-4) plays an essential role in T cell homeostasis by restraining immune responses. AG and GG genotypes of donor CTLA-4 SNP rs4553808 in patients after unrelated donor hematopoietic stem cell transplantations (HSCT) have been shown to be an independent predictor of inferior relapse-free survival (RFS) and overall survival (OS) compared with those with the AA genotype, in single-center studies. We tested the hypothesis that SNP rs4553808 is associated with RFS, OS, nonrelapse mortality (NRM) and the cumulative incidence of acute graft-versus-host disease (GVHD) and chronic GVHD in adults with acute myeloid leukemia and advanced myelodysplastic syndrome undergoing a first 8/8 or 7/8 HLA-matched unrelated donor HSCT. Multivariable analysis adjusting for relevant donor and recipient characteristics showed no significant association between SNP rs4553808 and OS, RFS, NRM, and incidence of acute and chronic GVHD. An exploratory analysis of other CTLA-4 SNPs, as well as studying the interaction with antithymocyte globulin, also demonstrated no significant associations. Our results indicate that CTLA-4 SNPs are not associated with HSCT outcomes.
Published by Elsevier Inc.
0 Communities
1 Members
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16 MeSH Terms