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Article: Activation of Ras-dependent Elk-1 activity by MLL-AF4 family fusion oncoproteins

TitleActivation of Ras-dependent Elk-1 activity by MLL-AF4 family fusion oncoproteins
Authors
Issue Date2010
PublisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/exphem
Citation
Experimental Hematology, 2010, v. 38 n. 6, p. 481-488 How to Cite?
AbstractObjective: Mixed lineage leukemia (MLL) gene rearrangement is commonly observed in human leukemias. Many of the resultant MLL fusion proteins are found correlated with Ras signaling. Nevertheless, Ras mutations have only been reported in a small subset of MLL-rearranged leukemia. With the potential of developing new therapeutic regimens targeting Ras signaling pathway, we studied the role of MLL-AF4 family fusions and MLL-septin family fusions in the activation of Ras signaling in leukemogenesis. Materials and Methods: Elk-1-driven luciferase reporter system was used to study the role of MLL-AF4, MLL-AF5q31, MLL-LAF4, MLL-CDCrel, MLL-MSF, and MLL-Septin 6 in the activation of Ras signaling. Dominant negative Ras S17N mutant and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor U0126 were employed to demonstrate the involvement of Ras and MEK in this transactivation event. The activation of endogenous Ras/MEK signaling pathway by MLL fusion proteins in leukemia cell lines was also addressed by immunoblot analysis and small interfering RNA knockdown approach. Results: We demonstrated that MLL-AF4, MLL-AF5q31, and MLL-LAF4 activated Elk-1 transcription factor, one of the major downstream effectors of Ras. This activation was abolished in the presence of dominant negative Ras or MEK inhibitor U0126, indicating the requirements of Ras and MEK. We further showed that endogenous MEK is phosphorylated in a MLL-AF4-expressing leukemia cell line, whereas depletion of MLL-AF4 by small interfering RNA reduced the phospho-MEK level. Conclusion: Our findings suggest that MLL-AF4 family fusion oncoproteins can activate Elk-1 through Ras/MEK/extracellular signal-regulated kinase (ERK) pathway and strongly support the role of Ras signaling in the pathogenesis of MLL-rearranged leukemia. © 2010 ISEH - Society for Hematology and Stem Cells.
Persistent Identifierhttp://hdl.handle.net/10722/126714
ISSN
2015 Impact Factor: 2.303
2015 SCImago Journal Rankings: 1.341
ISI Accession Number ID
Funding AgencyGrant Number
Research Grants Council of the Hong Kong Special Administrative Region, ChinaHKU7304/04M
Funding Information:

We thank Dr. Olaf Heidenreich for the SEM cell line; Dr. CW Eric So for the helpful comments and discussion; Dr. Ngai Cheung and Mr. Cary So for the technical assistance and advice. This project was supported by the grant from Research Grants Council of the Hong Kong Special Administrative Region, China (HKU7304/04M).

References

 

DC FieldValueLanguage
dc.contributor.authorNg, MHJen_HK
dc.contributor.authorNg, RKen_HK
dc.contributor.authorKong, CTen_HK
dc.contributor.authorJin, DYen_HK
dc.contributor.authorChan, LCen_HK
dc.date.accessioned2010-10-31T12:44:15Z-
dc.date.available2010-10-31T12:44:15Z-
dc.date.issued2010en_HK
dc.identifier.citationExperimental Hematology, 2010, v. 38 n. 6, p. 481-488en_HK
dc.identifier.issn0301-472Xen_HK
dc.identifier.urihttp://hdl.handle.net/10722/126714-
dc.description.abstractObjective: Mixed lineage leukemia (MLL) gene rearrangement is commonly observed in human leukemias. Many of the resultant MLL fusion proteins are found correlated with Ras signaling. Nevertheless, Ras mutations have only been reported in a small subset of MLL-rearranged leukemia. With the potential of developing new therapeutic regimens targeting Ras signaling pathway, we studied the role of MLL-AF4 family fusions and MLL-septin family fusions in the activation of Ras signaling in leukemogenesis. Materials and Methods: Elk-1-driven luciferase reporter system was used to study the role of MLL-AF4, MLL-AF5q31, MLL-LAF4, MLL-CDCrel, MLL-MSF, and MLL-Septin 6 in the activation of Ras signaling. Dominant negative Ras S17N mutant and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor U0126 were employed to demonstrate the involvement of Ras and MEK in this transactivation event. The activation of endogenous Ras/MEK signaling pathway by MLL fusion proteins in leukemia cell lines was also addressed by immunoblot analysis and small interfering RNA knockdown approach. Results: We demonstrated that MLL-AF4, MLL-AF5q31, and MLL-LAF4 activated Elk-1 transcription factor, one of the major downstream effectors of Ras. This activation was abolished in the presence of dominant negative Ras or MEK inhibitor U0126, indicating the requirements of Ras and MEK. We further showed that endogenous MEK is phosphorylated in a MLL-AF4-expressing leukemia cell line, whereas depletion of MLL-AF4 by small interfering RNA reduced the phospho-MEK level. Conclusion: Our findings suggest that MLL-AF4 family fusion oncoproteins can activate Elk-1 through Ras/MEK/extracellular signal-regulated kinase (ERK) pathway and strongly support the role of Ras signaling in the pathogenesis of MLL-rearranged leukemia. © 2010 ISEH - Society for Hematology and Stem Cells.en_HK
dc.languageengen_HK
dc.publisherElsevier Inc. The Journal's web site is located at http://www.elsevier.com/locate/exphemen_HK
dc.relation.ispartofExperimental Hematologyen_HK
dc.subject.meshGene Knockdown Techniques-
dc.subject.meshMyeloid-Lymphoid Leukemia Protein - metabolism-
dc.subject.meshOncogene Proteins, Fusion - metabolism-
dc.subject.meshets-Domain Protein Elk-1 - metabolism-
dc.subject.meshras Proteins - metabolism-
dc.titleActivation of Ras-dependent Elk-1 activity by MLL-AF4 family fusion oncoproteinsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0301-472X&volume=38&issue=6&spage=481&epage=488&date=2010&atitle=Activation+of+Ras-dependent+Elk-1+activity+by+MLL-AF4+family+fusion+oncoproteinsen_HK
dc.identifier.emailNg, RK:rayng@pathology.hku.hken_HK
dc.identifier.emailJin, DY:dyjin@hkucc.hku.hken_HK
dc.identifier.emailChan, LC:chanlc@hkucc.hku.hken_HK
dc.identifier.authorityNg, RK=rp00273en_HK
dc.identifier.authorityJin, DY=rp00452en_HK
dc.identifier.authorityChan, LC=rp00373en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.exphem.2010.03.014en_HK
dc.identifier.pmid20362031-
dc.identifier.scopuseid_2-s2.0-77952957383en_HK
dc.identifier.hkuros173959en_HK
dc.identifier.hkuros175624-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77952957383&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume38en_HK
dc.identifier.issue6en_HK
dc.identifier.spage481en_HK
dc.identifier.epage488en_HK
dc.identifier.eissn1873-2399-
dc.identifier.isiWOS:000278178000008-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridNg, MHJ=27067825500en_HK
dc.identifier.scopusauthoridNg, RK=7102153853en_HK
dc.identifier.scopusauthoridKong, CT=7102017292en_HK
dc.identifier.scopusauthoridJin, DY=7201973614en_HK
dc.identifier.scopusauthoridChan, LC=7403540707en_HK
dc.identifier.citeulike6959101-

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