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

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• 作者：Katrin K Fleischmann (1)
  Philipp Pagel (2)
  Irene Schmid (1)
  Adelbert A Roscher (3)
  
• 关键词：Acute myeloid leukemia ; MLL ; AF9 ; Fusion gene ; siRNA ; Gene expression ; Therapeutic targets ; Molecular processes ; SCH39166 ; Ecopipam
• 刊名：Molecular Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：13
• 期：1
• 全文大小：760 KB
• 作者单位：Katrin K Fleischmann (1)
  Philipp Pagel (2)
  Irene Schmid (1)
  Adelbert A Roscher (3)
  
  1. Children鈥檚 Research Center, Division of Pediatric Hematology and Oncology, Dr. von Hauner Children鈥檚 Hospital, Ludwig-Maximilians-Universit盲t M眉nchen, Lindwurmstrasse 2a, M眉nchen, 80337, Germany
  2. Lehrstuhl f眉r Genomorientierte Bioinformatik, Technische Universit盲t M眉nchen, Maximus-von-Imhof-Forum 3, Freising, D-85354, Germany
  3. Children鈥檚 Research Center, Dr. von Hauner Children鈥檚 Hospital, Ludwig-Maximilians-Universit盲t M眉nchen, Lindwurmstrasse 2a, M眉nchen, 80337, Germany
  
• ISSN：1476-4598

文摘

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.