| Leukemia represents a small percentage of human cancer, accounting for about 5% of all cases of cancer in adults, but, interestingly, for about 50% of all cases of cancer in children. The behavior of leukemia is often regulated by the chromosomal translocation that initiates disease, which not only predict outcome but also define therapy to be used. The fusion proteins as a result of chromosomal translocation often offer attractive opportunities for therapeutic intervention and small molecules targeting the leukemogenesis machinery have demonstrated their clinical importance. The potential side effect of such inhibitors can be predicted by studying the protein-protein interaction under normal settings. Our study describes such an effort to predict potential side effect of such interface-disrupting molecules under normal settings by addressing the role of a particular protein-protein interaction in normal hematopoiesis.;MLL1 (Mixed Lineage Leukemia 1) translocations encode protein fusions retaining the N-terminus of MLL1, which interacts with a tumor suppressor, Menin. This interaction is thought to be essential for leukemogenesis, thus is a promising drug target. However, wild-type MLL1 plays a critical role in sustaining hematopoietic stem cells (HSCs), thus the disruption of the Menin-MLL1 interaction would be expected to ablate normal hematopoiesis. We set out to address the importance of the Menin-MLL1 interaction during normal hematopoiesis, including hematopoietic stem cells (HSCs), B- cells and hematopoietic stem and progenitor (HSPC) homing. Specifically we undertook genetic, genomic and functional approaches and showed that rather than always working as a complex, Menin and MLL1 regulate distinct pathways during normal hematopoiesis, particularly in HSC maintenance and B-cell differentiation. In B-cells, Menin or MLL1-regulated genes can be classified into three categories: a relatively small group of co- regulated genes including Hoxa9 and Meis1 but also Mecom and Eya1, and much larger categories of Menin-only-regulated and MLL1-only-regulated genes. Our results highlight the large degree of independence of Menin and MLL1 and demonstrate that Menin is not a requisite cofactor for MLL1 during normal hematopoiesis. Furthermore, our data support the development of Menin-MLL1 interface disrupting drugs as a safe and selective strategy for leukemia with MLL1-fusion. |
