MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia
- 10 July 2014
- journal article
- Published by American Society of Hematology in Blood
- Vol. 124 (2), 263-272
- https://doi.org/10.1182/blood-2013-09-525741
Abstract
A rare location, t(6;11)(q27;q23) (MLL-AF6), is associated with poor outcome in childhood acute myeloid leukemia (AML). The described mechanism by which MLL-AF6, through constitutive self-association and in cooperation with DOT-1L, activates aberrant gene expression does not explain the biological differences existing between t(6;11)-rearranged and other MLL-positive patients nor their different clinical outcome. Here, we show that AF6 is expressed in the cytoplasm of healthy bone marrow cells and controls rat sarcoma viral oncogene (RAS)-guanosine triphosphate (GTP) levels. By contrast, in MLL-AF6-rearranged cells, AF6 is found localized in the nucleus, leading to aberrant activation of RAS and of its downstream targets. Silencing MLL-AF6, we restored AF6 localization in the cytoplasm, thus mediating significant reduction of RAS-GTP levels and of cell clonogenic potential. The rescue of RAS-GTP levels after MLL-AF6 and AF6 co-silencing confirmed that MLL-AF6 oncoprotein potentiates the activity of the RAS pathway through retention of AF6 within the nucleus. Exposure of MLL-AF6-rearranged AML blasts to tipifarnib, a RAS inhibitor, leads to cell autophagy and apoptosis, thus supporting RAS targeting as a novel potential therapeutic strategy in patients carrying t(6;11). Altogether, these data point to a novel role of the MLL-AF6 chimera and show that its gene partner, AF6, is crucial in AML development. Key Points MLL-AF6 leads to aberrant activation of RAS and its downstream targets. RAS targeting is a novel potential therapeutic strategy in AML patients carrying t(6;11).Keywords
This publication has 52 references indexed in Scilit:
- Model for MLL translocations in therapy-related leukemia involving topoisomerase IIβ-mediated DNA strand breaks and gene proximityProceedings of the National Academy of Sciences of the United States of America, 2012
- The Histone Demethylase KDM1A Sustains the Oncogenic Potential of MLL-AF9 Leukemia Stem CellsCancer Cell, 2012
- Loss of AF6/afadin, a marker of poor outcome in breast cancer, induces cell migration, invasiveness and tumor growthOncogene, 2011
- A Phase I Clinical-Pharmacodynamic Study of the Farnesyltransferase Inhibitor Tipifarnib in Combination with the Proteasome Inhibitor Bortezomib in Advanced Acute LeukemiasClinical Cancer Research, 2011
- Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesisGenes & Development, 2011
- Self-association mediated by the Ras association 1 domain of AF6 activates the oncogenic potential of MLL-AF6Blood, 2010
- Role of autophagy in cancerNature Reviews Cancer, 2007
- Autophagy suppresses tumor progression by limiting chromosomal instabilityGenes & Development, 2007
- Regulation of c-Src by binding to the PDZ domain of AF-6The EMBO Journal, 2007
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001