Leukaemia lineage specification caused by cell-specific Mll-Enl translocations

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Chromosomal translocations involving the Mixed-Lineage Leukaemia (MLL) gene are implicated in human leukaemias.
• MLL rearrangements are observed in both acute myelogenous and acute lymphoblastic leukaemias.

Purpose of the Study:

• To determine the specific hematopoietic cell contexts essential for MLL fusions to induce tumorigenesis.
• To investigate the role of cellular environment in MLL-associated leukaemogenesis.

Main Methods:

• Generation of mouse models with de novo Mll-associated translocations using Cre-loxP recombination.
• Induction of translocations in various hematopoietic cells: stem cells, progenitors, T cells, and B cells.
• Analysis of tumor development and MLL-fusion mRNA expression in different cellular contexts.

Main Results:

• Mll-Enl translocations initiated myeloid neoplasias when occurring in hematopoietic stem cells or progenitors.
• No tumors developed when Mll-Enl translocations were restricted to the B-cell compartment.
• Mll-Enl fusion mRNA was expressed in B-cell translocators, despite the absence of tumorigenesis.

Conclusions:

• A permissive cellular environment is crucial for the oncogenicity of MLL-associated translocations.
• The oncogenic potential of MLL-fusion proteins is context-dependent, not solely driven by the fusion event itself.
• These findings highlight a specific instructive role of MLL-fusion proteins in leukaemogenesis.