Menin Regulates the Function of Lymphoid Progenitors and Hematopoietic Stem Cells.

Menin is the product of the Men1 gene, a tumor suppressor gene that is mutated in patients with multiple endocrine neoplasia type I (MEN1). In addition to its effects in endocrine tissues, Menin interacts with the Mixed Lineage Leukemia (Mll) gene product as part of a multiprotein complex with H3K4 methyltransferase activity. Menin is required to mediate malignant transformation induced by Mll gene rearrangements, an activity associated with transcriptional activation of Homeobox (Hox) gene expression, presumably through epigenetic regulation. To explore the normal function of Menin in hematopoiesis, we studied bone marrow (BM) progenitors after inactivation of the Men1 gene in adult mice. Loss of Menin led to a modest reduction in peripheral blood neutrophil, lymphocyte and platelet counts. In the absence of hematopoietic stress, numbers of multilineage and myeloerythroid BM progenitors were preserved, but pro-B cells and downstream B lineage progenitor subsets were significantly decreased. Competitive BM transplantation assays revealed a marked defect in the function of Menin-deficient hematopoietic stem cells (HSCs), including long-term HSCs. Furthermore, Menin-deficient mice had impaired hematopoietic recovery after chemoablation with 5-fluorouracil. However, expression of Hox genes in BM HSCs was not impaired in the absence of Menin. These observations reveal an essential role of Menin in the homeostasis of hematopoietic stem and progenitor cells. Furthermore, they suggest that Menin may regulate normal hematopoiesis through mechanisms that are distinct from its role in Hox gene-dependent malignant transformation.