A novel lymphoid progenitor cell population (LSK(low)) is restricted by p18(INK4c).
The cyclin-dependent kinase inhibitor CDKN2C (p18(INK4c)) restrains self-renewal in hematopoietic stem cells (HSCs) and participates in the development and maturation of lymphoid cells. Deficiency in p18 predisposes mice and humans to hematopoietic lymphoid malignancies such as T-cell leukemia and multiple myeloma. However, the mechanism by which p18 regulates differentiation from HSCs to lymphoid cells is poorly understood. In this study, we found that a progenitor population characterized by its expression of surface markers, Lin(-) Sca-1(+) c-Kit(low) (LSK(low)), was markedly expanded in the bone marrow of p18 knock-out (p18(-/-)) mice. This novel population possessed lymphoid differentiation potential, but not myeloid differentiation potential, both in vitro and in vivo. Whereas LSK(low) cells and common lymphoid progenitors (CLPs) overlapped functionally in generating lymphoid cells, they were distinct cell populations, because they had different gene expression profiles. Unlike CLPs, LSK(low) cells did not express the interleukin-7 receptor. LSK(low) cells were derived from HSCs and were independent of the p18-deleted microenvironment. This cell population may represent a previously unappreciated transitional stage from HSCs to lymphoid progenitors that is strictly restricted by p18 under physiological conditions. Likewise, LSK(low) might serve as a new cellular target of lymphoid malignances in the absence of p18.
State Key Laboratory of Experimental Hematology, Tianjin, China; Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
Fang
F
Dong
State Key Laboratory of Experimental Hematology, Tianjin, China; Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. Electronic address: haosha@ihcams.ac.cn.
Sha
S
Hao
State Key Laboratory of Experimental Hematology, Tianjin, China; Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
Shihui
S
Ma
State Key Laboratory of Experimental Hematology, Tianjin, China; Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
Hui
H
Cheng
State Key Laboratory of Experimental Hematology, Tianjin, China; Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
Yajie
Y
Wang
Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Hunan, China.
Wen
W
Zhou
State Key Laboratory of Experimental Hematology, Tianjin, China; Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Department of Stem Cell & Regenerative Medicine, Peking Union Medical College, Tianjin, China.
Weiping
W
Yuan
State Key Laboratory of Experimental Hematology, Tianjin, China; Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Department of Stem Cell & Regenerative Medicine, Peking Union Medical College, Tianjin, China.
Hideo
H
Ema
State Key Laboratory of Experimental Hematology, Tianjin, China; Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China; Department of Stem Cell & Regenerative Medicine, Peking Union Medical College, Tianjin, China; Collaborative Innovation Center for Cancer Medicine, Tianjin, China. Electronic address: chengtao@ihcams.ac.cn.
Tao
T
Cheng
D000818:Animals; D015415:Biomarkers; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D060833:Cellular Microenvironment; D016000:Cluster Analysis; D003114:Colony-Forming Units Assay; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006085:Graft Survival; D016130:Immunophenotyping; D016131:Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism; D054503:Lymphoid Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D038041:Lymphopoiesis; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010641:Phenotype; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*
D015415:Biomarkers; D050763:Cyclin-Dependent Kinase Inhibitor p18; C085377:MATK protein, human; D016392:Proto-Oncogene Proteins pp60(c-src)