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Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) frequently comprises mutations in genes that cause perturbation in intracellular signaling pathways, thereby altering normal responses to growth factors and cytokines. Such oncogenic cellular signal transduction may be therapeutic if targeted directly or through epigenetic regulation. We treated 24 selected elderly AML patients with all-trans retinoic acid for 2 days before adding theophylline and the histone deacetylase inhibitor valproic acid (ClinicalTrials.gov NCT00175812; EudraCT no. 2004-001663-22), and sampled 11 patients for peripheral blood at day 0, 2 and 7 for single-cell analysis of basal level and signal-transduction responses to relevant myeloid growth factors (granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, interleukin-3, Flt3L, stem cell factor, erythropoietin, CXCL-12) on 10 signaling molecules (CREB, STAT1/3/5, p38, Erk1/2, Akt, c-Cbl, ZAP70/Syk and rpS6). Pretreatment analysis by unsupervised clustering and principal component analysis divided the patients into three distinguishable signaling clusters (non-potentiated, potentiated basal and potentiated signaling). Signal-transduction pathways were modulated during therapy and patients moved between the clusters. Patients with multiple leukemic clones demonstrated distinct stimulation responses and therapy-induced modulation. Individual signaling profiles together with clinical and hematological information may be used to early identify AML patients in whom epigenetic and signal-transduction targeted therapy is beneficial.
Authors:
Skavland, J; Jørgensen, K M; [1]  Hadziavdic, K; [2]  Hovland, R; [3]  Jonassen, I; [2]  Computational Biology Unit, Bergen Centre for Computational Science, University of Bergen, Bergen (Norway)]; Bruserud, Ø; Gjertsen, B T, E-mail: bjorn.gjertsen@med.uib.no [Hematology Section, Institute of Medicine, University of Bergen, Bergen (Norway); Hematology Section, Department of Medicine, Haukeland University Hospital, Bergen (Norway)]
  1. Hematology Section, Institute of Medicine, University of Bergen, Bergen (Norway)
  2. Department of Informatics, University of Bergen, Bergen (Norway)
  3. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen (Norway)
Publication Date:
Feb 01, 2011
Product Type:
Journal Article
Resource Relation:
Journal Name: Blood Cancer Journal; Journal Volume: 1; Journal Issue: 2; Other Information: PMCID: PMC3255270; PMID: 22829110; OAI: oai:pubmedcentral.nih.gov:3255270; Copyright (c) 2011 Macmillan Publishers Limited; This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/; Country of input: International Atomic Energy Agency (IAEA)
Subject:
60 APPLIED LIFE SCIENCES; 62 RADIOLOGY AND NUCLEAR MEDICINE; DISTURBANCES; ERYTHROPOIETIN; IN VIVO; LEUKOCYTES; LYMPHOKINES; MACROPHAGES; MYELOID LEUKEMIA; PATIENTS; PHOSPHORYLATION; POPULATIONS; RETINOIC ACID; SIGNALS; STEM CELLS; THERAPY
OSTI ID:
22343073
Country of Origin:
United Kingdom
Language:
English
Other Identifying Numbers:
Journal ID: ISSN 2044-5385; Other: PII: bcj20112; TRN: GB15$0108049407
Availability:
Available from http://dx.doi.org/10.1038/bcj.2011.2; Available from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255270
Submitting Site:
INIS
Size:
page(s) 4
Announcement Date:
Jun 19, 2015

Citation Formats

Skavland, J, Jørgensen, K M, Hadziavdic, K, Hovland, R, Jonassen, I, Computational Biology Unit, Bergen Centre for Computational Science, University of Bergen, Bergen (Norway)], Bruserud, Ø, Gjertsen, B T, E-mail: bjorn.gjertsen@med.uib.no [Hematology Section, Institute of Medicine, University of Bergen, Bergen (Norway), and Hematology Section, Department of Medicine, Haukeland University Hospital, Bergen (Norway)]. Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia. United Kingdom: N. p., 2011. Web. doi:10.1038/BCJ.2011.2.
Skavland, J, Jørgensen, K M, Hadziavdic, K, Hovland, R, Jonassen, I, Computational Biology Unit, Bergen Centre for Computational Science, University of Bergen, Bergen (Norway)], Bruserud, Ø, Gjertsen, B T, E-mail: bjorn.gjertsen@med.uib.no [Hematology Section, Institute of Medicine, University of Bergen, Bergen (Norway), & Hematology Section, Department of Medicine, Haukeland University Hospital, Bergen (Norway)]. Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia. United Kingdom. doi:10.1038/BCJ.2011.2.
Skavland, J, Jørgensen, K M, Hadziavdic, K, Hovland, R, Jonassen, I, Computational Biology Unit, Bergen Centre for Computational Science, University of Bergen, Bergen (Norway)], Bruserud, Ø, Gjertsen, B T, E-mail: bjorn.gjertsen@med.uib.no [Hematology Section, Institute of Medicine, University of Bergen, Bergen (Norway), and Hematology Section, Department of Medicine, Haukeland University Hospital, Bergen (Norway)]. 2011. "Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia." United Kingdom. doi:10.1038/BCJ.2011.2. https://www.osti.gov/servlets/purl/10.1038/BCJ.2011.2.
@misc{etde_22343073,
title = {Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia}
author = {Skavland, J, Jørgensen, K M, Hadziavdic, K, Hovland, R, Jonassen, I, Computational Biology Unit, Bergen Centre for Computational Science, University of Bergen, Bergen (Norway)], Bruserud, Ø, Gjertsen, B T, E-mail: bjorn.gjertsen@med.uib.no [Hematology Section, Institute of Medicine, University of Bergen, Bergen (Norway), and Hematology Section, Department of Medicine, Haukeland University Hospital, Bergen (Norway)]}
abstractNote = {Acute myeloid leukemia (AML) frequently comprises mutations in genes that cause perturbation in intracellular signaling pathways, thereby altering normal responses to growth factors and cytokines. Such oncogenic cellular signal transduction may be therapeutic if targeted directly or through epigenetic regulation. We treated 24 selected elderly AML patients with all-trans retinoic acid for 2 days before adding theophylline and the histone deacetylase inhibitor valproic acid (ClinicalTrials.gov NCT00175812; EudraCT no. 2004-001663-22), and sampled 11 patients for peripheral blood at day 0, 2 and 7 for single-cell analysis of basal level and signal-transduction responses to relevant myeloid growth factors (granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, interleukin-3, Flt3L, stem cell factor, erythropoietin, CXCL-12) on 10 signaling molecules (CREB, STAT1/3/5, p38, Erk1/2, Akt, c-Cbl, ZAP70/Syk and rpS6). Pretreatment analysis by unsupervised clustering and principal component analysis divided the patients into three distinguishable signaling clusters (non-potentiated, potentiated basal and potentiated signaling). Signal-transduction pathways were modulated during therapy and patients moved between the clusters. Patients with multiple leukemic clones demonstrated distinct stimulation responses and therapy-induced modulation. Individual signaling profiles together with clinical and hematological information may be used to early identify AML patients in whom epigenetic and signal-transduction targeted therapy is beneficial.}
doi = {10.1038/BCJ.2011.2}
journal = {Blood Cancer Journal}
issue = {2}
volume = {1}
journal type = {AC}
place = {United Kingdom}
year = {2011}
month = {Feb}
}