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Distinct pathways regulated by menin and by MLL1 in hematopoietic stem cells and developing B cells.

Publication TypeJournal Article
AuthorsLi, BE, Gan T., Meyerson M., Rabbitts TH, and Ernst P.
AbstractMixed Lineage Leukemia (MLL1) translocations encode fusion proteins retaining the N terminus of MLL1, which interacts with the tumor suppressor, menin. This interaction is essential for leukemogenesis and thus is a promising drug target. However, wild-type MLL1 plays a critical role in sustaining hematopoietic stem cells (HSCs); therefore, disruption of an essential MLL1 cofactor would be expected to obliterate normal hematopoiesis. Here we show that rather than working together as a complex, menin and MLL1 regulate distinct pathways during normal hematopoiesis, particularly in HSCs and B cells. We demonstrate the lack of genetic interaction between menin and MLL1 in steady-state or regenerative hematopoiesis and in B-cell differentiation despite the fact that MLL1 is critical for these processes. In B cells, menin- or MLL1-regulated genes can be classified into 3 categories: (1) a relatively small group of coregulated genes including previously described targets Hoxa9 and Meis1 but also Mecom and Eya1, and much larger groups of (2) exclusively menin-regulated and (3) exclusively MLL1-regulated genes. Our results highlight the large degree of independence of these 2 proteins and demonstrate that menin is not a requisite cofactor for MLL1 during normal hematopoiesis. Furthermore, our data support the development of menin-MLL1-disrupting drugs as safe and selective leukemia targeting agents.
Year of Publication2013
JournalBlood
Volume122
Issue12
Pages2039-46
Date Published (YYYY/MM/DD)2013/09/19
ISSN Number0006-4971
DOI10.1182/blood-2013-03-486647
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/23908472?dopt=Abstract