Menin-regulated genes in bone marrow B-cell progenitors

MLL1 translocations encode fusion proteins retaining the N-terminus of MLL1, which interacts with the tumor suppressor, menin. This interaction is essential for leukemogenesis, 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 three categories: 1) a relatively small group of co-regulated 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 two 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.

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Li BE, Gan T, Meyerson M, Rabbitts TH, Ernst P