MLL-ENL cooperates with SCF to transform primary avian multipotent cells

Area of Science:

• Hematology
• Molecular Biology
• Cancer Research

Background:

• Chromosomal translocations targeting the MLL gene produce fusion proteins implicated in acute leukaemias.
• Understanding how these MLL fusion proteins affect hematopoietic progenitor cells is critical for leukaemia research.

Purpose of the Study:

• To investigate the impact of MLL-AF9 and MLL-ENL fusion proteins on the proliferation and differentiation of primary hematopoietic progenitors.
• To determine the role of stem cell factor (SCF) in sustaining the growth of MLL fusion protein-transformed cells.

Main Methods:

• Introduction of MLL-AF9 and MLL-ENL fusion proteins into primary chicken bone marrow cells.
• Culturing transformed cells in the presence and absence of stem cell factor (SCF).
• Analysis of clonal cultures and induction of differentiation using a two-step protocol.

Main Results:

• Both MLL-AF9 and MLL-ENL induced sustained outgrowth of immature hematopoietic cells, dependent on SCF.
• Transformed cells exhibited multipotency, expressing markers for erythroid, myeloid, lymphoid, and stem cells, with extended in vitro lifespan.
• MLL-ENL transformed progenitors could undergo terminal erythroid or myeloid differentiation upon SCF withdrawal.
• MLL-ENL cooperated with v-Sea to induce multilineage leukaemia in vivo.

Conclusions:

• MLL fusion proteins promote the self-renewal of immature hematopoietic progenitors in an SCF-dependent manner.
• These transformed progenitors retain multipotency and can be induced to differentiate, suggesting a block in normal differentiation pathways.
• Activated receptor tyrosine kinases can cooperate with MLL fusion proteins to induce leukaemia, highlighting potential therapeutic targets.