Importance of a specific amino acid pairing for murine MLL leukemias driven by MLLT1/3 or AFF1/4 Journal Article

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Authors: Lokken, A. A.; Achille, N. J.; Chang, M. J.; Lin, J. J.; Kuntimaddi, A; Leach, B. I.; Malik, B.; Nesbit, J. B.; Zhang, S; Bushweller, J. H.; Zeleznik-Le, N. J.; Hemenway, C. S.
Article Title: Importance of a specific amino acid pairing for murine MLL leukemias driven by MLLT1/3 or AFF1/4
Abstract: Acute leukemias caused by translocations of the MLL gene at chromosome 11 band q23 (11q23) are characterized by a unique gene expression profile. More recently, data from several laboratories indicate that the most commonly encountered MLL fusion proteins, MLLT1, MLLT3, and AFF1 are found within a molecular complex that facilitates the elongation phase of mRNA transcription. Mutational analyses suggest that interaction between the MLLT1/3 proteins and AFF family proteins are required for experimental transformation of hematopoietic progenitor cells (HPCs). Here, we define a specific pairing of two amino acids that creates a salt bridge between MLLT1/3 and AFF proteins that is critically important for MLL-mediated transformation of HPCs. Our findings, coupled with the newly defined structure of MLLT3 in complex with AFF1, should facilitate the development of small molecules that block this amino acid interaction and interfere with the activity of the most common MLL oncoproteins.
Journal Title: Leukemia research
Volume: 38
Issue: 11
ISSN: 1873-5835; 0145-2126
Publisher: Elsevier Inc  
Journal Place: England
Date Published: 2014
Start Page: 1309
End Page: 1315
Language: eng
DOI/URL:

10.1016/j.leukres.2014.08.010
Notes: LR: 20150401; CI: Copyright (c) 2014; GR: CA 098459/CA/NCI NIH HHS/United States; GR: CA 155328/CA/NCI NIH HHS/United States; GR: R01 CA155328/CA/NCI NIH HHS/United States; JID: 7706787; 0 (Aff4 protein, mouse); 0 (Amino Acids); 0 (DNA-Binding Proteins); 0 (Mllt1 protein, mouse); 0 (Mllt3 protein, mouse); 0 (Nuclear Proteins); 0 (Transcription Factors); NIHMS624516; OID: NLM: NIHMS624516 [Available on 11/01/15]; OID: NLM: PMC4253547 [Available on 11/01/15]; OTO: NOTNLM; PMCR: 2015/11/01 00:00; 2014/03/28 [received]; 2014/08/06 [revised]; 2014/08/16 [accepted]; 2014/08/24 [aheadofprint]; ppublish