ALM

Oncogenic NRAS Primes Primary Acute Myeloid Leukemia Cells for Differentiation

Publication Date: April 22, 2015
Journal: PLOS ONE
Authors: Cornelia Brendel, Sabine Teichler, Axel Millahn, Thorsten Stiewe, et al
Volume: 10
Issue: 4
Pages: e0123181
DOI: https://dx.plos.org/10.1371/journal.pone.0123181
Publisher URL: http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0123181
PubMed: http://www.ncbi.nlm.nih.gov/pubmed/25901794
PubMed Central: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406710
Europe PMC: http://europepmc.org/abstract/MED/25901794
Web of Science: 000353331500047
Scopus: 84930672014
Mendeley: http://www.mendeley.com/research/oncogenic-nras-primes-primary-acute-myeloid-leukemia-cells-differentiation

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CiteULike17 May 03:26 UTC

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Mendeley 1819 Apr 21:09 UTC

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{"title"=>"Oncogenic NRAS primes primary acute myeloid leukemia cells for differentiation", "type"=>"journal", "authors"=>[{"first_name"=>"Cornelia", "last_name"=>"Brendel", "scopus_author_id"=>"6603965680"}, {"first_name"=>"Sabine", "last_name"=>"Teichler", "scopus_author_id"=>"24463947200"}, {"first_name"=>"Axel", "last_name"=>"Millahn", "scopus_author_id"=>"56674743300"}, {"first_name"=>"Thorsten", "last_name"=>"Stiewe", "scopus_author_id"=>"6602734956"}, {"first_name"=>"Michael", "last_name"=>"Krause", "scopus_author_id"=>"56932629700"}, {"first_name"=>"Kathleen", "last_name"=>"Stabla", "scopus_author_id"=>"24462739500"}, {"first_name"=>"Petra", "last_name"=>"Ross", "scopus_author_id"=>"57197393205"}, {"first_name"=>"Minh", "last_name"=>"Huynh", "scopus_author_id"=>"7004928371"}, {"first_name"=>"Thomas", "last_name"=>"Illmer", "scopus_author_id"=>"6701801332"}, {"first_name"=>"Marco", "last_name"=>"Mernberger", "scopus_author_id"=>"35337300100"}, {"first_name"=>"Christina", "last_name"=>"Barckhausen", "scopus_author_id"=>"55653360100"}, {"first_name"=>"Andreas", "last_name"=>"Neubauer", "scopus_author_id"=>"7102006569"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84930672014", "sgr"=>"84930672014", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0123181", "pmid"=>"25901794", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pui"=>"604612744"}, "id"=>"5d91350d-99d7-37e6-965b-150f266589a3", "abstract"=>"RAS mutations are frequently found among acute myeloid leukemia patients (AML), generating a constitutively active signaling protein changing cellular proliferation, differentiation and apoptosis. We have previously shown that treatment of AML patients with high-dose cytarabine is preferentially beneficial for those harboring oncogenic RAS. On the basis of a murine AML cell culture model, we ascribed this effect to a RAS-driven, p53-dependent induction of differentiation. Hence, in this study we sought to confirm the correlation between RAS status and differentiation of primary blasts obtained from AML patients. The gene expression signature of AML blasts with oncogenic NRAS indeed corresponded to a more mature profile compared to blasts with wildtype RAS, as demonstrated by gene set enrichment analysis (GSEA) and real-time PCR analysis of myeloid ecotropic viral integration site 1 homolog (MEIS1) in a unique cohort of AML patients. In addition, in vitro cell culture experiments with established cell lines and a second set of primary AML cells showed that oncogenic NRAS mutations predisposed cells to cytarabine (AraC) driven differentiation. Taken together, our findings show that AML with inv(16) and NRAS mutation have a differentiation gene signature, supporting the notion that NRAS mutation may predispose leukemic cells to AraC induced differentiation. We therefore suggest that promotion of differentiation pathways by specific genetic alterations could explain the superior treatment outcome after therapy in some AML patient subgroups. Whether a differentiation gene expression status may generally predict for a superior treatment outcome in AML needs to be addressed in future studies.", "link"=>"http://www.mendeley.com/research/oncogenic-nras-primes-primary-acute-myeloid-leukemia-cells-differentiation", "reader_count"=>18, "reader_count_by_academic_status"=>{"Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>5, "Student > Master"=>3, "Student > Bachelor"=>2, "Lecturer"=>1}, "reader_count_by_user_role"=>{"Researcher"=>6, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>5, "Student > Master"=>3, "Student > Bachelor"=>2, "Lecturer"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>4, "Medicine and Dentistry"=>3, "Agricultural and Biological Sciences"=>9, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"United States"=>1, "Germany"=>1}, "group_count"=>0}

ORCID01 Apr 15:37 UTC

Europe PMC Database Citations | Further Information

{"UNIPROT"=>5}

PubMed Central31 Jan 09:21 UTC

PubMed Central

Scopus 310 Jan 09:13 UTC

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Web of Science®05 Jan 13:00 UTC

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Journal Comments 123 Oct 13:09 UTC

Journal Comments | Further Information

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Nature22 May 00:15 UTC

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Figshare 11202 Apr 19:43 UTC

Figshare

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{"files"=>["https://ndownloader.figshare.com/files/2035780"], "description"=>"GSEA: gene set enrichment analysisAML patient cohorts used in this study.", "links"=>[], "tags"=>["Differentiation RAS mutations", "myeloid leukemia patients", "NRAS mutation", "Acute Myeloid Leukemia Cells", "meis", "integration site 1 homolog", "Oncogenic NRAS Primes", "pcr", "AML patients", "cell culture experiments", "gsea", "oncogenic NRAS mutations", "murine AML cell culture model", "differentiation gene expression status", "gene expression signature", "AML patient subgroups", "differentiation gene signature", "treatment Outcome"], "article_id"=>1391398, "categories"=>["Biological Sciences"], "users"=>["Cornelia Brendel", "Sabine Teichler", "Axel Millahn", "Thorsten Stiewe", "Michael Krause", "Kathleen Stabla", "Petra Ross", "Minh Huynh", "Thomas Illmer", "Marco Mernberger", "Christina Barckhausen", "Andreas Neubauer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0123181.t001", "stats"=>{"downloads"=>2, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_AML_patient_cohorts_used_in_this_study_/1391398", "title"=>"AML patient cohorts used in this study.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-04-22 03:51:05"}
{"files"=>["https://ndownloader.figshare.com/files/2035778"], "description"=>"(A) May-Grünwald-Giemsa staining of HL-60 and U937 (wtRAS) cells 48h after AraC treatment at indicated doses. (B) CD14 expression in HL-60 and U937 cells 48 h after AraC-treatment at indicated doses as determined by quantitative real-time PCR. GAPDH was used for normalization. The graph shows the median with 95% confidence interval. Results were normalized to the respective control of each cell line. **: p = 0.002 (Student’s t-test).", "links"=>[], "tags"=>["Differentiation RAS mutations", "myeloid leukemia patients", "NRAS mutation", "Acute Myeloid Leukemia Cells", "meis", "integration site 1 homolog", "Oncogenic NRAS Primes", "pcr", "AML patients", "cell culture experiments", "gsea", "oncogenic NRAS mutations", "murine AML cell culture model", "differentiation gene expression status", "gene expression signature", "AML patient subgroups", "differentiation gene signature", "treatment Outcome"], "article_id"=>1391396, "categories"=>["Biological Sciences"], "users"=>["Cornelia Brendel", "Sabine Teichler", "Axel Millahn", "Thorsten Stiewe", "Michael Krause", "Kathleen Stabla", "Petra Ross", "Minh Huynh", "Thomas Illmer", "Marco Mernberger", "Christina Barckhausen", "Andreas Neubauer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0123181.g002", "stats"=>{"downloads"=>0, "page_views"=>30, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_AraC_induces_differentiation_in_the_mt_NRAS_harboring_AML_cell_line_HL_60_/1391396", "title"=>"AraC induces differentiation in the mtNRAS harboring AML cell line HL-60.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-22 03:51:05"}
{"files"=>["https://ndownloader.figshare.com/files/2035783", "https://ndownloader.figshare.com/files/2035784", "https://ndownloader.figshare.com/files/2035785", "https://ndownloader.figshare.com/files/2035786", "https://ndownloader.figshare.com/files/2035787", "https://ndownloader.figshare.com/files/2035788", "https://ndownloader.figshare.com/files/2035789", "https://ndownloader.figshare.com/files/2035790"], "description"=>"<div>RAS mutations are frequently found among acute myeloid leukemia patients (AML), generating a constitutively active signaling protein changing cellular proliferation, differentiation and apoptosis. We have previously shown that treatment of AML patients with high-dose cytarabine is preferentially beneficial for those harboring oncogenic RAS. On the basis of a murine AML cell culture model, we ascribed this effect to a RAS-driven, p53-dependent induction of differentiation. Hence, in this study we sought to confirm the correlation between RAS status and differentiation of primary blasts obtained from AML patients. The gene expression signature of AML blasts with oncogenic NRAS indeed corresponded to a more mature profile compared to blasts with wildtype RAS, as demonstrated by gene set enrichment analysis (GSEA) and real-time PCR analysis of myeloid ecotropic viral integration site 1 homolog (MEIS1) in a unique cohort of AML patients. In addition, in vitro cell culture experiments with established cell lines and a second set of primary AML cells showed that oncogenic NRAS mutations predisposed cells to cytarabine (AraC) driven differentiation. Taken together, our findings show that AML with inv(16) and NRAS mutation have a differentiation gene signature, supporting the notion that NRAS mutation may predispose leukemic cells to AraC induced differentiation. We therefore suggest that promotion of differentiation pathways by specific genetic alterations could explain the superior treatment outcome after therapy in some AML patient subgroups. Whether a differentiation gene expression status may generally predict for a superior treatment outcome in AML needs to be addressed in future studies.</div>", "links"=>[], "tags"=>["Differentiation RAS mutations", "myeloid leukemia patients", "NRAS mutation", "Acute Myeloid Leukemia Cells", "meis", "integration site 1 homolog", "Oncogenic NRAS Primes", "pcr", "AML patients", "cell culture experiments", "gsea", "oncogenic NRAS mutations", "murine AML cell culture model", "differentiation gene expression status", "gene expression signature", "AML patient subgroups", "differentiation gene signature", "treatment Outcome"], "article_id"=>1391401, "categories"=>["Biological Sciences"], "users"=>["Cornelia Brendel", "Sabine Teichler", "Axel Millahn", "Thorsten Stiewe", "Michael Krause", "Kathleen Stabla", "Petra Ross", "Minh Huynh", "Thomas Illmer", "Marco Mernberger", "Christina Barckhausen", "Andreas Neubauer"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0123181.s001", "https://dx.doi.org/10.1371/journal.pone.0123181.s002", "https://dx.doi.org/10.1371/journal.pone.0123181.s003", "https://dx.doi.org/10.1371/journal.pone.0123181.s004", "https://dx.doi.org/10.1371/journal.pone.0123181.s005", "https://dx.doi.org/10.1371/journal.pone.0123181.s006", "https://dx.doi.org/10.1371/journal.pone.0123181.s007", "https://dx.doi.org/10.1371/journal.pone.0123181.s008"], "stats"=>{"downloads"=>9, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Oncogenic_NRAS_Primes_Primary_Acute_Myeloid_Leukemia_Cells_for_Differentiation/1391401", "title"=>"Oncogenic NRAS Primes Primary Acute Myeloid Leukemia Cells for Differentiation", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-04-22 03:51:05"}
{"files"=>["https://ndownloader.figshare.com/files/2035776"], "description"=>"(A-E) Enrichment plots as obtained by GSEA software for the gene sets CROONQUIST_NRAS_SIGNALING_UP, positive control; IVANOVA HEMATO-POIESIS_MATURE_CELL; JAATINEN_HEMATOPOIETIC_STEM _CELL _UP; BENPORATH_MYC_TARGETS_WITH_EBOX; IVANOVA_HEMATOPOIESIS_INTER-MEDIATE_PROGENITOR. Primary AML blasts harboring wtNRAS were compared with mtNRAS (12/13 or 61) blasts. (F) Relative expression of MEIS1 in primary AML blasts carrying wtRAS or mtNRAS as examined by real-time PCR. The graph shows the median with 95% confidence interval. Results were normalized to MEIS1 expression of mtNRAS blasts. GAPDH expression served as internal control. *: p = 0.025 (Mann Whitney test).", "links"=>[], "tags"=>["Differentiation RAS mutations", "myeloid leukemia patients", "NRAS mutation", "Acute Myeloid Leukemia Cells", "meis", "integration site 1 homolog", "Oncogenic NRAS Primes", "pcr", "AML patients", "cell culture experiments", "gsea", "oncogenic NRAS mutations", "murine AML cell culture model", "differentiation gene expression status", "gene expression signature", "AML patient subgroups", "differentiation gene signature", "treatment Outcome"], "article_id"=>1391394, "categories"=>["Biological Sciences"], "users"=>["Cornelia Brendel", "Sabine Teichler", "Axel Millahn", "Thorsten Stiewe", "Michael Krause", "Kathleen Stabla", "Petra Ross", "Minh Huynh", "Thomas Illmer", "Marco Mernberger", "Christina Barckhausen", "Andreas Neubauer"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0123181.g001", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Impact_of_NRAS_status_on_the_transcriptome_of_primary_AML_blasts_/1391394", "title"=>"Impact of NRAS status on the transcriptome of primary AML blasts.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-04-22 03:51:05"}

PMC Usage Stats 195417 Jan 22:00 UTC

PMC Usage Stats | Further Information

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{"unique-ip"=>"41", "full-text"=>"41", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"9"}
{"unique-ip"=>"22", "full-text"=>"23", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2020", "month"=>"10"}
{"unique-ip"=>"18", "full-text"=>"19", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"11"}
{"unique-ip"=>"15", "full-text"=>"15", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2020", "month"=>"12"}

Relative Metric04 Apr 11:47 UTC

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{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}

F1000Prime27 Jan 13:27 UTC

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