Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia

Area of Science:

• Hematology
• Cancer Biology
• Epigenetics

Background:

• The MLL/AF4 fusion gene characterizes a high-risk pro-B acute lymphoblastic leukemia (ALL).
• Relapse in MLL/AF4 ALL can involve a lineage switch to acute myeloid leukemia (AML), conferring resistance to therapies and poor prognosis.

Purpose of the Study:

• To investigate the mechanisms underlying lineage switching in MLL/AF4-positive ALL.
• To identify key molecular drivers of the transition from lymphoid to myeloid leukemia phenotypes.

Main Methods:

• Comparative analysis of oncogene fusion breakpoints in matched lymphoid and myeloid relapse samples.
• Assessment of chromatin accessibility and transcriptional reprogramming during lineage switching.
• Investigation of the role of chromatin modifiers, such as CHD4, in MLL/AF4 ALL relapse.

Main Results:

• Myeloid relapses maintained shared oncogene fusion breakpoints with the original lymphoid leukemia.
• Lineage switching was associated with significant alterations in chromatin accessibility and gene expression, including alternative splicing.
• The chromatin modifier CHD4 showed altered expression, splicing, or mutation in relapsed myeloid phenotypes.
• Perturbation of CHD4 induced myeloid gene expression in MLL/AF4+ cell models.

Conclusions:

• Lineage switching in MLL/AF4 ALL is characterized by impaired lymphoid differentiation maintenance.
• Disrupted epigenetic regulation, particularly involving CHD4 and other chromatin modifiers, drives and sustains the myeloid leukemia phenotype during relapse.