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

Elena Manara1, Emma Baron1, Claudia Tregnago1

  • 1Women and Child Health Department, Hematology-Oncology Laboratory, Instituto di Ricerca Pediatrica, University of Padova, Padova, Italy;

Blood
|April 4, 2014
PubMed

Insights

The MLL-AF6 fusion protein in acute myeloid leukemia (AML) causes the AF6 protein to move to the nucleus, activating the RAS pathway. Inhibiting RAS shows promise for treating this rare AML subtype.

Area of Science:

  • Hematology
  • Molecular Biology
  • Cancer Research

Background:

  • The t(6;11)(q27;q23) translocation, forming the MLL-AF6 fusion, is linked to poor prognosis in childhood acute myeloid leukemia (AML).
  • Existing models of MLL-AF6's mechanism do not fully explain the distinct clinical outcomes observed in t(6;11)-rearranged AML compared to other MLL-positive leukemias.

Purpose of the Study:

  • To elucidate the specific role of AF6 protein localization in the pathogenesis of MLL-AF6-rearranged AML.
  • To investigate the functional consequences of aberrant AF6 nuclear localization on cellular signaling pathways.
  • To explore potential therapeutic strategies targeting the RAS pathway in t(6;11) AML.

Main Methods:

  • Immunofluorescence microscopy to determine AF6 subcellular localization in healthy and MLL-AF6-rearranged cells.
  • Gene silencing techniques (siRNA) to modulate MLL-AF6 and AF6 expression.
  • Assessment of RAS-guanosine triphosphate (GTP) levels.
  • Evaluation of cell clonogenic potential.
  • Treatment of AML blasts with tipifarnib, a RAS inhibitor, followed by analysis of cell death pathways (autophagy and apoptosis).

Main Results:

  • In healthy bone marrow cells, AF6 is cytoplasmic and regulates RAS-GTP levels.
  • In MLL-AF6-rearranged AML cells, AF6 is aberrantly localized in the nucleus, leading to increased RAS-GTP levels and downstream target activation.
  • Silencing MLL-AF6 restored cytoplasmic AF6 localization, reduced RAS-GTP levels, and decreased cell clonogenicity.
  • Co-silencing of MLL-AF6 and AF6 rescued RAS-GTP levels, confirming MLL-AF6's role in nuclear AF6 retention and RAS pathway potentiation.
  • Tipifarnib treatment induced autophagy and apoptosis in MLL-AF6-rearranged AML blasts.

Conclusions:

  • The MLL-AF6 chimera potentiates RAS pathway activity by sequestering AF6 in the nucleus.
  • AF6 nuclear retention is a critical mechanism in the development of MLL-AF6-rearranged AML.
  • Targeting the RAS pathway with inhibitors like tipifarnib represents a promising therapeutic avenue for patients with t(6;11) AML.

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