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

Authors: Shih, S. J.; Fass, J.; Buffalo, V.; Lin, D.; Singh, S. P.; Diaz, M. O.; Vaughan, A. T.
Article Title: 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/beta-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 Title: British journal of haematology
Volume: 159
Issue: 1
ISSN: 1365-2141; 0007-1048
Publisher: Blackwell Publishing Ltd  
Journal Place: England
Date Published: 2012
Start Page: 50
End Page: 57
Language: eng
Notes: LR: 20130416; CI: (c) 2012; GR: CA10504/CA/NCI NIH HHS/United States; JID: 0372544; 0 (DNA-Binding Proteins); 0 (MLL protein, human); 0 (Transcription Factors); 149025-06-9 (Myeloid-Lymphoid Leukemia Protein); 23214-92-8 (Doxorubicin); 50-18-0 (Cyclophosphamide); 53-03-2 (Prednisone); 57-22-7 (Vincristine); EC (Cytidine Deaminase); CHOP protocol; NIHMS391121; OID: NLM: NIHMS391121 [Available on 10/01/13]; OID: NLM: PMC3444640 [Available on 10/01/13]; PMCR: 2013/10/01 00:00; 2012/04/06 [received]; 2012/06/25 [accepted]; 2012/07/30 [aheadofprint]; ppublish