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Blood DOI:10.1182/blood-2013-03-486647

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

Publication TypeJournal Article
Year of Publication2013
AuthorsLi, BE, Gan, T, Meyerson, M, Rabbitts, TH, Ernst, P
JournalBlood
Volume122
Issue12
Pages2039-46
Date Published2013 Sep 19
ISSN1528-0020
KeywordsAnimals, B-Lymphocytes, Cell Differentiation, Epistasis, Genetic, Female, Gene Expression Regulation, Hematopoiesis, Hematopoietic Stem Cells, Lymphopoiesis, Mice, Mice, Transgenic, Myeloid-Lymphoid Leukemia Protein, Proto-Oncogene Proteins, Signal Transduction
Abstract

Mixed 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.

URLhttp://bloodjournal.hematologylibrary.org/cgi/pmidlookup?view=long&pmid=23908472
DOI10.1182/blood-2013-03-486647
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23908472?dopt=Abstract

Alternate JournalBlood
PubMed ID23908472
PubMed Central IDPMC3778547
Grant ListP20 RR016437 / RR / NCRR NIH HHS / United States
/ / Medical Research Council / United Kingdom
R01 HL090036 / HL / NHLBI NIH HHS / United States
CA23108 / CA / NCI NIH HHS / United States
MR/J000612/1 / / Medical Research Council / United Kingdom
P30 CA023108 / CA / NCI NIH HHS / United States
P20-RR16437 / RR / NCRR NIH HHS / United States
HL090036 / HL / NHLBI NIH HHS / United States
G0600914 / / Medical Research Council / United Kingdom