Submitted March 31, 2008
Accepted September 3, 2008
Defective Notch activation in microenvironment leads to myeloproliferative disease
Young-Woong Kim, Bon-Kyoung Koo, Hyun-Woo Jeong, Mi-Jeong Yoon, Ran Song, Juhee Shin, Dae-Chul Jeong, Sun-Hee Kim, and Young-Yun Kong*
Department of Life Science, Pohang University of Science and Technology, Pohang, Korea, Republic of
Department of Pediatrics, Catholic University of Korea, Seoul, Korea, Republic of
Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of
School of Biological Science, College of Natural Sciences, Seoul National University, Seoul, Korea, Republic of
* Corresponding author; email: ykong{at}snu.ac.kr.
Despite the great importance of non-hematopoietic cells constituting the microenvironment for normal hematopoiesis, the cellular interactions between non-hematopoietic 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 two independent Mib1 conditional knockout (CKO) mouse lines each developed an MPD, with gradual accumulations of immature granulocytes. The mutant mice showed hepatosplenomegaly, anemia, granulocytosis, and leukocyte infiltration in multiple organs, and finally died around 20 weeks of age. Surprisingly, 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 non-hematopoietic 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.
