Multiple clonal MLL fusions in a patient receiving CHOP-based chemotherapy

Area of Science:

• Hematology
• Molecular Biology
• Oncology

Background:

• Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma.
• MLL gene rearrangements are implicated in various hematologic malignancies, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
• Understanding MLL rearrangements in DLBCL is crucial for identifying novel therapeutic targets.

Purpose of the Study:

• To analyze MLL rearrangements in a patient with diffuse large B-cell lymphoma undergoing chemotherapy.
• To identify novel MLL fusion genes and their potential clinical implications.
• To investigate the formation mechanisms and clonal behavior of MLL rearrangements.

Main Methods:

• Inverse polymerase chain reaction (PCR) targeting MLL exon 12.
• Parallel sequencing.
• Custom algorithm for data analysis.

Main Results:

• Thirteen MLL rearrangements were detected, with five generating MLL fusion genes.
• Identified MLL-MLLT3 and novel fusions, including MLL-NKD1, which targets a pathway involved in leukaemic cell proliferation.
• The majority of fusions showed clonal persistence post-chemotherapy, suggesting a survival advantage.
• MLL breakpoints clustered at a specific site with increased C to T transitions, indicating potential AICDA involvement.
• MLL demonstrated interaction with multiple fusion partners, similar to AML and ALL.

Conclusions:

• MLL rearrangements can occur in DLBCL and generate diverse fusion genes, including novel ones.
• The identified MLL fusions may confer a survival advantage to leukaemic clones.
• A specific MLL breakpoint site is susceptible to fragmentation, potentially involving AICDA deregulation.