Defective Notch activation in microenvironment leads to myeloproliferative disease.
Despite the great importance of nonhematopoietic cells constituting the microenvironment for normal hematopoiesis, the cellular interactions between nonhematopoietic cells themselves are largely unknown. Using the Cre-loxP system in mice to inactivate Mind bomb-1 (Mib1), an essential component for Notch ligand endocytosis, here we show that the development of an MPD is dependent on defective Notch activation in the microenvironment. Our 2 independent Mib1 conditional knockout (CKO) mouse lines each developed a myeloproliferative disease (MPD), with gradual accumulations of immature granulocytes. The mutant mice showed hepatosplenomegaly, anemia, granulocytosis, and leukocyte infiltration in multiple organs and finally died at approximately 20 weeks of age. We were surprised to find that the transplantation of wild-type bone marrow cells into the Mib1-null microenvironment resulted in a de novo MPD. Moreover, by introducing the constitutively active intracellular domain of Notch1 in the Mib1-null background, we show that active Notch1 expression in the Mib1-null microenvironment significantly suppressed the disease progression, suggesting that the MPD development in the Mib1 CKO mice is due to defective Notch activation in the nonhematopoietic cells. These findings demonstrate that normal hematopoiesis absolutely requires Notch activation through the Notch ligand-receptor interaction between microenvironmental cells themselves and shed light on the microenvironment that fosters hematopoietic disorders.
Kim
Young-Woong
YW
Department of Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk, South Korea.
Koo
Bon-Kyoung
BK
Jeong
Hyun-Woo
HW
Yoon
Mi-Jeong
MJ
Song
Ran
R
Shin
Juhee
J
Jeong
Dae-Chul
DC
Kim
Sun-Hee
SH
Kong
Young-Yun
YY
D000818:Animals; D002478:Cells, Cultured; D018450:Disease Progression; D004705:Endocytosis / Q000235:genetics; D005110:Extracellular Space / Q000235:genetics / Q000378:metabolism; D006098:Granulocytes / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D051880:Receptors, Notch; C470629:MIB1 protein, mouse; D044767:Ubiquitin-Protein Ligases