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

Journal article

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.

Authors: Li, B; Gan, T; Meyerson, M; Rabbitts, T; Ernst, P

• Journal: Blood
• Volume: 122
• Issue: 12
• Pages: 2039-2046
• Publication date: 2013-09-01
• DOI: 10.1182/blood-2013-03-486647
• EISSN: 1528-0020
• ISSN: 0006-4971
• Language: English
• Keywords: Proto-Oncogene Proteins; Myeloid-Lymphoid Leukemia Protein; Signal Transduction; Lymphopoiesis; Hematopoiesis; Mice; Hematopoietic Stem Cells; Epistasis, Genetic; Mice, Transgenic; Gene Expression Regulation; Cell Differentiation; Female; B-Lymphocytes; Animals