AKT Signaling as a Novel Factor Associated with In Vitro Resistance of Human AML to Gemtuzumab Ozogamicin
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{"title"=>"AKT Signaling as a Novel Factor Associated with In Vitro Resistance of Human AML to Gemtuzumab Ozogamicin", "type"=>"journal", "authors"=>[{"first_name"=>"David B.", "last_name"=>"Rosen", "scopus_author_id"=>"7202022762"}, {"first_name"=>"Kimberly H.", "last_name"=>"Harrington", "scopus_author_id"=>"55520824700"}, {"first_name"=>"James A.", "last_name"=>"Cordeiro", "scopus_author_id"=>"54979976900"}, {"first_name"=>"Ling Y.", "last_name"=>"Leung", "scopus_author_id"=>"55553189800"}, {"first_name"=>"Santosh", "last_name"=>"Putta", "scopus_author_id"=>"6603879985"}, {"first_name"=>"Norman", "last_name"=>"Lacayo", "scopus_author_id"=>"6507333888"}, {"first_name"=>"George S.", "last_name"=>"Laszlo", "scopus_author_id"=>"7006110341"}, {"first_name"=>"Chelsea J.", "last_name"=>"Gudgeon", "scopus_author_id"=>"55519710600"}, {"first_name"=>"Donna E.", "last_name"=>"Hogge", "scopus_author_id"=>"7006269287"}, {"first_name"=>"Rachael E.", "last_name"=>"Hawtin", "scopus_author_id"=>"35268582900"}, {"first_name"=>"Alessandra", "last_name"=>"Cesano", "scopus_author_id"=>"7003304252"}, {"first_name"=>"Roland B.", "last_name"=>"Walter", "scopus_author_id"=>"18438853700"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"23320091", "doi"=>"10.1371/journal.pone.0053518", "pui"=>"368093939", "issn"=>"19326203", "sgr"=>"84872174451", "scopus"=>"2-s2.0-84872174451"}, "id"=>"6f469f45-997c-3d87-93f5-ad66c9f6e4cb", "abstract"=>"Gemtuzumab ozogamicin (GO), an immunoconjugate between an anti-CD33 antibody and a calicheamicin-γ(1) derivative, induces remissions and improves survival in a subset of patients with acute myeloid leukemia (AML). As the mechanisms underlying GO and calicheamicin-γ(1) resistance are incompletely understood, we herein used flow cytometry-based single cell network profiling (SCNP) assays to study cellular responses of primary human AML cells to GO. Our data indicate that the extent of DNA damage is quantitatively impacted by CD33 expression and drug efflux activity. However, although DNA damage is required for GO-induced cytotoxicity, it is not sufficient for effective cell kill, suggesting that downstream anti-apoptotic pathways may function as relevant resistance mechanisms. Supporting this notion, we found activated PI3K/AKT signaling to be associated with GO resistance in vitro in primary AML cells. Consistently, the investigational AKT inhibitor MK-2206 significantly sensitized various human AML cells to GO or free calicheamicin-γ(1) with particularly pronounced effects in otherwise GO or free calicheamicin-γ(1)-resistant cells. Likewise, MK-2206 also sensitized primary AML cells to calicheamicin-γ(1). Together, our findings illustrate the capacity of SCNP assays to discover chemotherapy-related biological pathways and signaling networks relevant to GO-induced genotoxic stress. The identification of AKT signaling as being associated with GO resistance in vitro may provide a novel approach to improve the in vivo efficacy of GO/calicheamicin-γ(1) and, by extrapolation, other DNA damage-based therapeutics.", "link"=>"http://www.mendeley.com/research/akt-signaling-novel-factor-associated-vitro-resistance-human-aml-gemtuzumab-ozogamicin-1", "reader_count"=>11, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>4, "Student > Doctoral Student"=>1, "Student > Postgraduate"=>2, "Student > Master"=>3}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>4, "Student > Doctoral Student"=>1, "Student > Postgraduate"=>2, "Student > Master"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>3, "Medicine and Dentistry"=>3, "Agricultural and Biological Sciences"=>4}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>4}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"United States"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/512603"], "description"=>"<p><b>Abbreviations:</b> BM, bone marrow; ITD, internal tandem duplication; NK, normal karyotype; PB, peripheral blood; WT, wild-type.</p>1<p>% Blasts among viable mononuclear cells.</p>", "links"=>[], "tags"=>["aml", "specimen"], "article_id"=>183085, "categories"=>["Cancer", "Genetics", "Pharmacology"], "users"=>["David B. Rosen", "Kimberly H. Harrington", "James A. Cordeiro", "Ling Y. Leung", "Santosh Putta", "Norman Lacayo", "George S. Laszlo", "Chelsea J. Gudgeon", "Donna E. Hogge", "Rachael E. Hawtin", "Alessandra Cesano", "Roland B. Walter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0053518.t001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Primary_AML_Patient_and_Specimen_Characteristics_/183085", "title"=>"Primary AML Patient and Specimen Characteristics.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-01-08 00:51:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/512553"], "description"=>"<p><b>Abbreviations:</b> MFI, mean fluorescence intensity; NA, not available (insufficient sample material).</p>*<p>CD33 MFI are shown for the Qdot605 fluorophore scale. For AML-11, this value was converted from CD33-PE expression due to insufficient sample for CD33-Qdot605 assessment (see “<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053518#s2\" target=\"_blank\">Materials and Methods</a>”).</p>", "links"=>[], "tags"=>["aml"], "article_id"=>183035, "categories"=>["Cancer", "Genetics", "Pharmacology"], "users"=>["David B. Rosen", "Kimberly H. Harrington", "James A. Cordeiro", "Ling Y. Leung", "Santosh Putta", "Norman Lacayo", "George S. Laszlo", "Chelsea J. Gudgeon", "Donna E. Hogge", "Rachael E. Hawtin", "Alessandra Cesano", "Roland B. Walter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0053518.t002", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_GO_induced_Apoptosis_Cell_Death_and_947_H2AX_in_Primary_AML_Specimens_/183035", "title"=>"GO-induced Apoptosis/Cell Death and γH2AX in Primary AML Specimens.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-01-08 00:50:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/511864"], "description"=>"<p>Scheme depicts the presumed mechanism of action of GO in CD33<sup>+</sup> AML cells <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053518#pone.0053518-Walter1\" target=\"_blank\">[5]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053518#pone.0053518-Linenberger1\" target=\"_blank\">[11]</a>. Experimentally measured components in our studies are shown in red: CD33 expression levels; drug efflux pump activity; γH2AX (extent of DNA damage); survival signaling pathways (PI3K/AKT, MEK/ERK, and JAK/STAT pathway); and cleaved PARP and cell membrane integrity (apoptosis/cell death).</p>", "links"=>[], "tags"=>["characterization", "go-induced", "cytotoxicity"], "article_id"=>182348, "categories"=>["Cancer", "Genetics", "Pharmacology"], "users"=>["David B. Rosen", "Kimberly H. Harrington", "James A. Cordeiro", "Ling Y. Leung", "Santosh Putta", "Norman Lacayo", "George S. Laszlo", "Chelsea J. Gudgeon", "Donna E. Hogge", "Rachael E. Hawtin", "Alessandra Cesano", "Roland B. Walter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0053518.g001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functional_characterization_of_GO_induced_cytotoxicity_in_CD33_cells_/182348", "title"=>"Functional characterization of GO-induced cytotoxicity in CD33<sup>+</sup> cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-08 00:39:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/512285"], "description"=>"<p>Various doses of the allosteric AKT inhibitor, MK-2206, were incubated with increasing concentrations of GO in (<b>A</b>) HL-60, (<b>B</b>) NB4, (<b>C</b>) TF-1, and (<b>D</b>) KG-1 cells. For KG-1 cells, conditions including drug efflux inhibitor PK11195 are also shown. After 3 days, viability (left-side panel) and cell numbers (right-side panel) was determined by flow cytometry. *<i>P</i><0.05 as compared to medium alone; **<i>P</i><0.01 as compared to medium alone; ***<i>P</i><0.001 as compared to medium alone; ****<i>P</i><0.0001 as compared to medium alone.</p>", "links"=>[], "tags"=>["akt", "inhibition", "go-induced", "cytotoxicity", "aml", "lines"], "article_id"=>182760, "categories"=>["Cancer", "Genetics", "Pharmacology"], "users"=>["David B. Rosen", "Kimberly H. Harrington", "James A. Cordeiro", "Ling Y. Leung", "Santosh Putta", "Norman Lacayo", "George S. Laszlo", "Chelsea J. Gudgeon", "Donna E. Hogge", "Rachael E. Hawtin", "Alessandra Cesano", "Roland B. Walter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0053518.g005", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_AKT_inhibition_on_GO_induced_cytotoxicity_in_human_AML_cell_lines_in_vitro_/182760", "title"=>"Effect of AKT inhibition on GO-induced cytotoxicity in human AML cell lines <i>in vitro</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-08 00:46:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/511975"], "description"=>"<p>(<b>A</b>) Correlation between CD33 expression and GO-induced DNA damage, as quantified by measurement of γH2AX levels 6 hours after drug exposure. (<b>B</b>) Correlation between CD33 expression and GO-induced cytotoxicity after 48 hours of drug exposure. Samples resistant to GO (as defined by <15% GO-induced apoptosis/cell death 24 hours after drug exposure) are shown in bold. Note: the CD33-QDot605 MFI for AML-11 was converted from CD33 PE MFI, as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053518#s2\" target=\"_blank\">Materials and Methods</a>.</p>", "links"=>[], "tags"=>["cd33", "go-induced", "dna"], "article_id"=>182453, "categories"=>["Cancer", "Genetics", "Pharmacology"], "users"=>["David B. Rosen", "Kimberly H. Harrington", "James A. Cordeiro", "Ling Y. Leung", "Santosh Putta", "Norman Lacayo", "George S. Laszlo", "Chelsea J. Gudgeon", "Donna E. Hogge", "Rachael E. Hawtin", "Alessandra Cesano", "Roland B. Walter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0053518.g002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Relationship_between_CD33_level_and_GO_induced_DNA_damage_and_cytotoxicity_/182453", "title"=>"Relationship between CD33 level and GO-induced DNA damage and cytotoxicity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-08 00:40:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/512064"], "description"=>"<p>GO-induced γH2AX (x-axis) and apoptosis (y-axis) at 6 hours (top row), 24 hours (middle row), and 48 hours (bottom row) in specimens AML-09, AML-10, and AML-07, exemplifying the observed response patterns in primary AML. Note: the apoptosis markers shown (y-axis) are cleaved caspase-3 for 6 hour data and cleaved PARP for 24 and 48 hour data; see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053518#pone.0053518.s002\" target=\"_blank\">Figure S2</a> for a demonstration of concordance between cleaved caspase-3 and cleaved PARP apoptosis markers.</p>", "links"=>[], "tags"=>["examples", "resistant", "aml"], "article_id"=>182542, "categories"=>["Cancer", "Genetics", "Pharmacology"], "users"=>["David B. Rosen", "Kimberly H. Harrington", "James A. Cordeiro", "Ling Y. Leung", "Santosh Putta", "Norman Lacayo", "George S. Laszlo", "Chelsea J. Gudgeon", "Donna E. Hogge", "Rachael E. Hawtin", "Alessandra Cesano", "Roland B. Walter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0053518.g003", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Representative_examples_of_GO_sensitive_and_resistant_AML_specimens_/182542", "title"=>"Representative examples of GO sensitive and resistant AML specimens.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-08 00:42:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/279416", "https://ndownloader.figshare.com/files/279463", "https://ndownloader.figshare.com/files/279494", "https://ndownloader.figshare.com/files/279542", "https://ndownloader.figshare.com/files/279591", "https://ndownloader.figshare.com/files/279637", "https://ndownloader.figshare.com/files/279681", "https://ndownloader.figshare.com/files/279737"], "description"=>"<div><p>Gemtuzumab ozogamicin (GO), an immunoconjugate between an anti-CD33 antibody and a calicheamicin-γ<sub>1</sub> derivative, induces remissions and improves survival in a subset of patients with acute myeloid leukemia (AML). As the mechanisms underlying GO and calicheamicin-γ<sub>1</sub> resistance are incompletely understood, we herein used flow cytometry-based single cell network profiling (SCNP) assays to study cellular responses of primary human AML cells to GO. Our data indicate that the extent of DNA damage is quantitatively impacted by CD33 expression and drug efflux activity. However, although DNA damage is required for GO-induced cytotoxicity, it is not sufficient for effective cell kill, suggesting that downstream anti-apoptotic pathways may function as relevant resistance mechanisms. Supporting this notion, we found activated PI3K/AKT signaling to be associated with GO resistance <em>in vitro</em> in primary AML cells. Consistently, the investigational AKT inhibitor MK-2206 significantly sensitized various human AML cells to GO or free calicheamicin-γ<sub>1</sub> with particularly pronounced effects in otherwise GO or free calicheamicin-γ<sub>1</sub> -resistant cells. Likewise, MK-2206 also sensitized primary AML cells to calicheamicin-γ<sub>1</sub>. Together, our findings illustrate the capacity of SCNP assays to discover chemotherapy-related biological pathways and signaling networks relevant to GO-induced genotoxic stress. The identification of AKT signaling as being associated with GO resistance <em>in vitro</em> may provide a novel approach to improve the <em>in vivo</em> efficacy of GO/calicheamicin-γ<sub>1</sub> and, by extrapolation, other DNA damage-based therapeutics.</p> </div>", "links"=>[], "tags"=>["akt", "signaling", "aml", "gemtuzumab", "ozogamicin"], "article_id"=>115086, "categories"=>["Cancer", "Genetics", "Pharmacology"], "users"=>["David B. Rosen", "Kimberly H. Harrington", "James A. Cordeiro", "Ling Y. Leung", "Santosh Putta", "Norman Lacayo", "George S. Laszlo", "Chelsea J. Gudgeon", "Donna E. Hogge", "Rachael E. Hawtin", "Alessandra Cesano", "Roland B. Walter"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0053518.s001", "https://dx.doi.org/10.1371/journal.pone.0053518.s002", "https://dx.doi.org/10.1371/journal.pone.0053518.s003", "https://dx.doi.org/10.1371/journal.pone.0053518.s004", "https://dx.doi.org/10.1371/journal.pone.0053518.s005", "https://dx.doi.org/10.1371/journal.pone.0053518.s006", "https://dx.doi.org/10.1371/journal.pone.0053518.s007", "https://dx.doi.org/10.1371/journal.pone.0053518.s008"], "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/AKT_Signaling_as_a_Novel_Factor_Associated_with_In_Vitro_Resistance_of_Human_AML_to_Gemtuzumab_Ozogamicin__/115086", "title"=>"AKT Signaling as a Novel Factor Associated with <em>In Vitro</em> Resistance of Human AML to Gemtuzumab Ozogamicin", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-01-08 01:24:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/512191"], "description"=>"<p>Plots of signaling log<sub>2</sub>-fold responses: FLT3L induced p-S6 (X-axis) vs. SCF induced p-AKT (top) or SCF induced p-S6 (bottom). Samples are coded by <i>in vitro</i> GO response (sensitive: green symbols; resistant: red symbols).</p>", "links"=>[], "tags"=>["signaling", "aml"], "article_id"=>182670, "categories"=>["Cancer", "Genetics", "Pharmacology"], "users"=>["David B. Rosen", "Kimberly H. Harrington", "James A. Cordeiro", "Ling Y. Leung", "Santosh Putta", "Norman Lacayo", "George S. Laszlo", "Chelsea J. Gudgeon", "Donna E. Hogge", "Rachael E. Hawtin", "Alessandra Cesano", "Roland B. Walter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0053518.g004", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Growth_factor_cytokine_induced_signaling_in_primary_AML_specimens_/182670", "title"=>"Growth factor/cytokine-induced signaling in primary AML specimens.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-08 00:44:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/512461"], "description"=>"<p>Density gradient-purified mononuclear cells from 3 patients with AML (AML-13, AML-14, and AML-15) were incubated with 2 doses of calicheamicin-γ<sub>1</sub> in the presence or absence of MK-2206 (1 µM) as indicated. After 3 days, viability was determined by flow cytometry.</p>", "links"=>[], "tags"=>["akt", "inhibition", "cytotoxicity", "aml", "cells"], "article_id"=>182936, "categories"=>["Cancer", "Genetics", "Pharmacology"], "users"=>["David B. Rosen", "Kimberly H. Harrington", "James A. Cordeiro", "Ling Y. Leung", "Santosh Putta", "Norman Lacayo", "George S. Laszlo", "Chelsea J. Gudgeon", "Donna E. Hogge", "Rachael E. Hawtin", "Alessandra Cesano", "Roland B. Walter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0053518.g006", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_AKT_inhibition_on_calicheamicin_1_induced_cytotoxicity_in_primary_AML_cells_in_vitro_/182936", "title"=>"Effect of AKT inhibition on calicheamicin-γ<sub>1</sub>-induced cytotoxicity in primary AML cells <i>in vitro</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-01-08 00:48:56"}

PMC Usage Stats | Further Information

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Relative Metric

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