The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression

Abstract

Menin is the product of the tumor suppressor gene Men1 that is mutated in the inherited tumor syndrome multiple endocrine neoplasia type 1 (MEN1). Menin has been shown to interact with SET-1 domain-containing histone 3 lysine 4 (H3K4) methyltransferases including mixed lineage leukemia proteins to regulate homeobox (Hox) gene expression in vitro. Using conditional Men1 knockout mice, we have investigated the requirement for menin in hematopoiesis and myeloid transformation. Men1 excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white blood cell count. Menin directly activates Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitating methylation of H3K4, and recruiting the methylated H3K4 binding protein chd1 to the locus. Consistent with signaling downstream of menin, ectopic expression of both Hoxa9 and Meis1 rescues colony formation defects in Men1-excised bone marrow. Moreover, Men1 excision also suppresses proliferation of leukemogenic mixed lineage leukemia-AF9 fusionprotein-transformed myeloid cells and Hoxa9 expression. These studies uncover an important role for menin in both normal hematopoiesis and myeloid transformation and provide a mechanistic understanding of menin's function in these processes that may be used for therapy. multiple endocrine neoplasia type 1 ͉ mixed lineage leukemia ͉ Men1 gene ͉ histone lysine methylation

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

“…123 The MLL complex requires the proteins MEN1 and PSIP1 to interact with chromatin. Indeed, excision of Men1 potently inhibits the proliferation of MLL-MLLT3-transformed cells and Hoxa9 expression in mice, 124 and similarly, knockdown of Psip1 impaired Hoxa9 expression. 28 This raises the possibility to block the function of Men1 or PSIP1 as a new targeted therapy in MLL rearrangements.…”

Phosphorylation of the Menin Tumor Suppressor Protein on Serine 543 and Serine 583

“…The MLL-menin interaction is essential for MLL-dependent leukemogenesis (28,29). We subsequently extended the area of known menin-regulated genes by demonstrating that menin interacts with MLL to cooperatively regulate the expression of the cyclin-dependent kinase inhibitors p27…”

Epigenetic regulations in hematopoietic Hox code

“…It is easily concluded that chromosomal translocation results in development of MLL fusion oncogenes and accordingly, mis-expression of Hox genes. However, numerous studies have shown that overexpression of MLL fusion oncoproteins in normal ES and bone marrow cells first promotes nonmalignant expansion of myeloid precursors and Hox deregulation, and then is followed by accumulation of malignant cells (Dobson et al, 1999;Kumar et al, 2004;Yokoyama et al, 2005;Chen et al, 2006). The long latency in vivo and monoclonal nature of the leukemias suggest that secondary genetic transformation is required for the development of leukemia (Dobson et al, 1999;Johnson et al, 2003).…”

“…Increasing evidence suggests that Hox transcription factors play a definitive role in normal proliferation and differentiation of hematopoietic cells (Magli et al, 1997;Owens and Hawley, 2002). Recent discoveries revealed that the menin and MLL-containing histone methyltransferase complex is required for Hox gene-dependent proliferation and differentiation of hematopoietic progenitors and leukemia stem cells (Hess, 2004;Hughes et al, 2004;Milne et al, 2005;Yokoyama et al, 2005Yokoyama et al, , 2010Chen et al, 2006;Thiel et al, 2010). These studies have given emphasis to epigenetic regulations in Hox-dependent hematopoiesis and leukemogenesis.…”