An Mll-dependent Hox program drives hematopoietic progenitor expansion

Chromosomal translocations disrupting the Mixed lineage leukemia (Mll) gene result in leukemia, with aberrant expression of some native Mll target genes (reviewed in). The Mll gene encodes a Trithorax-group chromatin regulator that is essential for the development of hematopoietic stem cells (HSCs) during embryogenesis. Like Trithorax, MLL positively regulates clustered homeodomain or Hox genes, yet the role of Hox genes collectively in the development of the mammalian hematopoietic system has been difficult to ascertain because of redundancy among Hox paralogs. Here, we show that in the absence of MLL, early hematopoietic progenitors develop despite reduced expression of HoxA, HoxB, and HoxC genes. However, these progenitors exhibit a marked reduction in their ability to generate hematopoietic colonies, a subsequent process requiring cell division and differentiation. Reactivation of a subset of Hox genes or, remarkably, reexpression of a single Hox gene in Mll-deficient progenitors rescued hematopoietic-colony frequency and growth. In contrast, expression of other MLL target genes such as Pitx2 or expression of anti-apoptotic BCL-2 failed to rescue hematopoietic-colony frequency. Furthermore, our results highlight a shared function of Hox proteins at this point in the development of the hematopoietic system.     

MLL targets SET domain methyltransferase activity to Hox gene promoters

MLL, the human homolog of Drosophila trithorax, maintains Hox gene expression in mammalian embryos and is rearranged in human leukemias resulting in Hox gene deregulation. How MLL or MLL fusion proteins regulate gene expression remains obscure. We show that MLL regulates target Hox gene expression through direct binding to promoter sequences. We further show that the MLL SET domain is a histone H3 lysine 4-specific methyltransferase whose activity is stimulated with acetylated H3 peptides. This methylase activity is associated with Hox gene activation and H3 (Lys4) methylation at cis-regulatory sequences in vivo. A leukemogenic MLL fusion protein that activates Hox expression had no effect on histone methylation, suggesting a distinct mechanism for gene regulation by MLL and MLL fusion proteins.     

MLL: How complex does it get?

The mixed lineage leukemia (MLL) gene encodes a very large nuclear protein homologous to Drosophila trithorax (trx). MLL is required for the proper maintenance of HOX gene expression during development and hematopoiesis. The exact regulatory mechanism of HOX gene expression by MLL is poorly understood, but it is believed that MLL functions at the level of chromatin organization. MLL was identified as a common target of chromosomal translocations associated with human acute leukemias. About 50 different MLL fusion partners have been isolated to date, and while similarities exist between groups of partners, there exists no unifying property shared by all the partners. MLL gene rearrangements are found in leukemias with both lymphoid and myeloid phenotypes and are often associated with infant and secondary leukemias. The immature phenotype of the leukemic blasts suggests an important role for MLL in the early stages of hematopoietic development. Mll homozygous mutant mice are embryonic lethal and exhibit deficiencies in yolk sac hematopoiesis. Recently, two different MLL-containing protein complexes have been isolated. These and other gain- and loss-of-function experiments have provided insight into normal MLL function and altered functions of MLL fusion proteins. This article reviews the progress made toward understanding the function of the wild-type MLL protein. While many advances in understanding this multifaceted protein have been made since its discovery, many challenging questions remain to be answered.