title: Hematopoietic stem cells are not the direct target of spontaneous leukemic transformation in p18(INK4C)-null reconstituted mice.
abstract: Cell cycle inhibitors are important regulators in normal tissue regeneration and disruption of the regulators are involved in cancer development. Our recent study showed that the absence of the CDK inhibitor p18(INK4C) (p18) enhances self-renewal of normal hematopoietic stem cell (HSC) in vivo, whereas previous studies by others showed an increased incidence of leukemogenesis in older p18-null mice. Here, we have examined potential leukemogenesis during experimentally induced regeneration of HSC in the absence of p18 in order to gauge the relation between these two processes. Reconstituted mice with p18-deficient HSCs under the condition of repetitive proliferative stress (serial transplantation) were followed for >3 years. T cell leukemia from the p18-/- origin was recapitulated 24 months after secondary transplantation. However, no myeloid leukemia was found in the recipients. The T cell leukemia-initiating cells (mainly in a CD3(lo) cell subset) did not share the same immunophenotype with normal HSCs and, in fact, the function of HSCs was significantly compromised with decreased abundance in the leukemic mice. Furthermore, we found that the p15 or p16 gene promoters were frequently methylated in the leukemic cells but not in HSCs. Our present study argues against the possibility of overgrowth of p18-null HSCs leading to a leukemic phenotype. The data also support the notion that p18 has an independent role in T cell maintenance such that CD3+ CD8+ cells, unlike HSCs, are more accessible to leukemogenic transformation after the loss of p18.
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Youzhong
authors.initials: Y
authors.lastname: Yuan
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Boyer
authors.forename: Xianmin
authors.initials: X
authors.lastname: Song
authors.forename: Shaonan
authors.initials: S
authors.lastname: Cao
authors.forename: Hongmei
authors.initials: H
authors.lastname: Shen
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000172:deficiency* / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D016130:Immunophenotyping; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
chemical_list: D050763:Cyclin-Dependent Kinase Inhibitor p18