MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia

Elena Manara, Emma Baron, Claudia Tregnago, Sanja Aveic, Valeria Bisio, Silvia Bresolin, Riccardo Masetti, Franco Locatelli, Giuseppe Basso, Martina Pigazzi

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Arare 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 cell sand 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.

Original languageEnglish
Pages (from-to)263-272
Number of pages10
JournalBlood
Volume124
Issue number2
DOIs
Publication statusPublished - Jul 10 2014

Fingerprint

Oncogene Fusion
Myeloid Leukemia
Guanosine Triphosphate
Acute Myeloid Leukemia
Fusion reactions
Chemical activation
tipifarnib
Cytoplasm
Rat control
Gerbillinae
Oncogene Proteins
Autophagy
Oncogenes
Gene expression
Bone Marrow Cells
Sarcoma
Bone
Sand
Genes
Cells

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Manara, E., Baron, E., Tregnago, C., Aveic, S., Bisio, V., Bresolin, S., ... Pigazzi, M. (2014). MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia. Blood, 124(2), 263-272. https://doi.org/10.1182/blood-2013-09-525741

MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia. / Manara, Elena; Baron, Emma; Tregnago, Claudia; Aveic, Sanja; Bisio, Valeria; Bresolin, Silvia; Masetti, Riccardo; Locatelli, Franco; Basso, Giuseppe; Pigazzi, Martina.

In: Blood, Vol. 124, No. 2, 10.07.2014, p. 263-272.

Research output: Contribution to journalArticle

Manara, E, Baron, E, Tregnago, C, Aveic, S, Bisio, V, Bresolin, S, Masetti, R, Locatelli, F, Basso, G & Pigazzi, M 2014, 'MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia', Blood, vol. 124, no. 2, pp. 263-272. https://doi.org/10.1182/blood-2013-09-525741
Manara, Elena ; Baron, Emma ; Tregnago, Claudia ; Aveic, Sanja ; Bisio, Valeria ; Bresolin, Silvia ; Masetti, Riccardo ; Locatelli, Franco ; Basso, Giuseppe ; Pigazzi, Martina. / MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia. In: Blood. 2014 ; Vol. 124, No. 2. pp. 263-272.
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AU - Bisio, Valeria

AU - Bresolin, Silvia

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