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

Abstract:

:MLL rearrangements were analysed in the blood of a patient receiving chemotherapy for diffuse large B-cell lymphoma using inverse polymerase chain reaction targeting exon 12, parallel sequencing and a custom algorithm design. Of thirteen MLL rearrangements detected, five were capable of generating MLL fusion genes, including MLL-MLLT3, the most common fusion in acute myeloid leukaemia (AML). Other fusions, all previously clinically unobserved, included MLL-NKD1, a fusion to the negative regulator of Wnt/β-catenin signaling, a pathway linked to leukaemic cell proliferation. The majority of the fusions exhibited clonal persistence from before treatment until 6 months post-chemotherapy, suggesting the fusions may confer a survival advantage to the mutant clone. MLL breakpoints were partly clustered at a specific location, indicating commonality in the process of their formation. Further, the same MLL breakpoint location exhibited a 50-100-fold increase in C to T transitions, consistent with attack by activation-induced cytidine deaminase (AICDA). As is also observed in AML and acute lymphoblastic leukaemia, in this single patient setting, MLL is capable of interacting with multiple fusion partners. This finding defines a discrete site of MLL susceptibility to fragmentation, linked to possible deregulation of AICDA function.

journal_name

Br J Haematol

authors

Shih SJ,Fass J,Buffalo V,Lin D,Singh SP,Diaz MO,Vaughan AT

doi

10.1111/j.1365-2141.2012.09248.x

subject

Has Abstract

pub_date

2012-10-01 00:00:00

pages

50-7

issue

1

eissn

0007-1048

issn

1365-2141

journal_volume

159

pub_type

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