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RNAi-mediated silencing of MLL-AF9 reveals leukemia-associated downstream targets and processes

BACKGROUND: The translocation t(9;11)(p22;q23) leading to the leukemogenic fusion gene MLL-AF9 is a frequent translocation in infant acute myeloid leukemia (AML). This study aimed to identify genes and molecular processes downstream of MLL-AF9 (alias MLL-MLLT3) which could assist to develop new targ...

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Autores principales: Fleischmann, Katrin K, Pagel, Philipp, Schmid, Irene, Roscher, Adelbert A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924703/
https://www.ncbi.nlm.nih.gov/pubmed/24517546
http://dx.doi.org/10.1186/1476-4598-13-27
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author Fleischmann, Katrin K
Pagel, Philipp
Schmid, Irene
Roscher, Adelbert A
author_facet Fleischmann, Katrin K
Pagel, Philipp
Schmid, Irene
Roscher, Adelbert A
author_sort Fleischmann, Katrin K
collection PubMed
description BACKGROUND: The translocation t(9;11)(p22;q23) leading to the leukemogenic fusion gene MLL-AF9 is a frequent translocation in infant acute myeloid leukemia (AML). This study aimed to identify genes and molecular processes downstream of MLL-AF9 (alias MLL-MLLT3) which could assist to develop new targeted therapies for such leukemia with unfavorable prognosis. METHODS: In the AML cell line THP1 which harbors this t(9;11) translocation, endogenous MLL-AF9 was silenced via siRNA while ensuring specificity of the knockdown and its efficiency on functional protein level. RESULTS: The differential gene expression profile was validated for leukemia-association by gene set enrichment analysis of published gene sets from patient studies and MLL-AF9 overexpression studies and revealed 425 differentially expressed genes. Gene ontology analysis was consistent with a more differentiated state of MLL-AF9 depleted cells, with involvement of a wide range of downstream transcriptional regulators and with defined functional processes such as ribosomal biogenesis, chaperone binding, calcium homeostasis and estrogen response. We prioritized 41 gene products as candidate targets including several novel and potentially druggable effectors of MLL-AF9 (AHR, ATP2B2, DRD5, HIPK2, PARP8, ROR2 and TAS1R3). Applying the antagonist SCH39166 against the dopamine receptor DRD5 resulted in reduced leukemic cell characteristics of THP1 cells. CONCLUSION: Besides potential new therapeutic targets, the described transcription profile shaped by MLL-AF9 provides an information source into the molecular processes altered in MLL aberrant leukemia.
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spelling pubmed-39247032014-02-15 RNAi-mediated silencing of MLL-AF9 reveals leukemia-associated downstream targets and processes Fleischmann, Katrin K Pagel, Philipp Schmid, Irene Roscher, Adelbert A Mol Cancer Research BACKGROUND: The translocation t(9;11)(p22;q23) leading to the leukemogenic fusion gene MLL-AF9 is a frequent translocation in infant acute myeloid leukemia (AML). This study aimed to identify genes and molecular processes downstream of MLL-AF9 (alias MLL-MLLT3) which could assist to develop new targeted therapies for such leukemia with unfavorable prognosis. METHODS: In the AML cell line THP1 which harbors this t(9;11) translocation, endogenous MLL-AF9 was silenced via siRNA while ensuring specificity of the knockdown and its efficiency on functional protein level. RESULTS: The differential gene expression profile was validated for leukemia-association by gene set enrichment analysis of published gene sets from patient studies and MLL-AF9 overexpression studies and revealed 425 differentially expressed genes. Gene ontology analysis was consistent with a more differentiated state of MLL-AF9 depleted cells, with involvement of a wide range of downstream transcriptional regulators and with defined functional processes such as ribosomal biogenesis, chaperone binding, calcium homeostasis and estrogen response. We prioritized 41 gene products as candidate targets including several novel and potentially druggable effectors of MLL-AF9 (AHR, ATP2B2, DRD5, HIPK2, PARP8, ROR2 and TAS1R3). Applying the antagonist SCH39166 against the dopamine receptor DRD5 resulted in reduced leukemic cell characteristics of THP1 cells. CONCLUSION: Besides potential new therapeutic targets, the described transcription profile shaped by MLL-AF9 provides an information source into the molecular processes altered in MLL aberrant leukemia. BioMed Central 2014-02-11 /pmc/articles/PMC3924703/ /pubmed/24517546 http://dx.doi.org/10.1186/1476-4598-13-27 Text en Copyright © 2014 Fleischmann et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.
spellingShingle Research
Fleischmann, Katrin K
Pagel, Philipp
Schmid, Irene
Roscher, Adelbert A
RNAi-mediated silencing of MLL-AF9 reveals leukemia-associated downstream targets and processes
title RNAi-mediated silencing of MLL-AF9 reveals leukemia-associated downstream targets and processes
title_full RNAi-mediated silencing of MLL-AF9 reveals leukemia-associated downstream targets and processes
title_fullStr RNAi-mediated silencing of MLL-AF9 reveals leukemia-associated downstream targets and processes
title_full_unstemmed RNAi-mediated silencing of MLL-AF9 reveals leukemia-associated downstream targets and processes
title_short RNAi-mediated silencing of MLL-AF9 reveals leukemia-associated downstream targets and processes
title_sort rnai-mediated silencing of mll-af9 reveals leukemia-associated downstream targets and processes
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924703/
https://www.ncbi.nlm.nih.gov/pubmed/24517546
http://dx.doi.org/10.1186/1476-4598-13-27
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