Menin regulates the function of hematopoietic stem cells and lymphoid progenitors.
Men1 is a tumor suppressor gene mutated in endocrine neoplasms. Besides its endocrine role, the Men1 gene product menin interacts with the mixed lineage leukemia (MLL) protein, a histone H3 lysine 4 methyltransferase. Although menin and MLL fusion proteins cooperate to activate Homeobox (Hox) gene expression during transformation, little is known about the normal hematopoietic functions of menin. Here, we studied hematopoiesis after Men1 ablation. Menin loss modestly impaired blood neutrophil, lymphocyte, and platelet counts. Without hematopoietic stress, multilineage and myelo-erythroid bone marrow progenitor numbers were preserved, while B lymphoid progenitors were decreased. In contrast, competitive transplantation revealed a marked functional defect of long-term hematopoietic stem cells (HSC) in the absence of menin, despite normal initial homing of progenitors to the bone marrow. HoxA9 gene expression was only modestly decreased in menin-deficient HSCs. These observations reveal a novel and essential role for menin in HSC homeostasis that was most apparent during situations of hematopoietic recovery, suggesting that menin regulates molecular pathways that are essential during the adaptive HSC response to stress.
Maillard
Ivan
I
Center for Stem Cell Biology, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA. imaillar@umich.edu
Chen
Ya-Xiong
YX
Friedman
Ann
A
Yang
Yuqing
Y
Tubbs
Anthony T
AT
Shestova
Olga
O
Pear
Warren S
WS
Hua
Xianxin
X
D000818:Animals; D016026:Bone Marrow Transplantation; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D007938:Leukemia / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D008214:Lymphocytes / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D009504:Neutrophils / Q000166:cytology; D010976:Platelet Count; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism
C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D016201:Receptors, Lymphocyte Homing