This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yuan, Y. Articles by Cheng, T. Search for Related Content PubMed PubMed Citation Articles by Yuan, Y. Articles by Cheng, T.

Hematopoietic Stem Cells Are Not the Direct Target of Spontaneous Leukemic Transformation in p18^INK4C-Null Reconstituted Mice

Department of Radiation Oncology, University of Pittsburgh School of Medicine and Stem Cell Biology Laboratory, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

Requests for reprints: Tao Cheng, Office Suite 2.42e, Research Pavilion at The Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Center Avenue, Pittsburgh, PA 15213-1863. Phone: 412-623-3249; Fax: 412-623-7778; E-mail: chengt{at}upmc.edu.

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. (Cancer Res 2006; 66(1): 343-51)

This article has been cited by other articles:

				C. R. Walkley and S. H. Orkin Rb is dispensable for self-renewal and multilineage differentiation of adult hematopoietic stem cells PNAS, June 13, 2006; 103(24): 9057 - 9062. [Abstract] [Full Text] [PDF]

				H. Yu, Y. Yuan, H. Shen, and T. Cheng Hematopoietic stem cell exhaustion impacted by p18INK4C and p21Cip1/Waf1 in opposite manners Blood, February 1, 2006; 107(3): 1200 - 1206. [Abstract] [Full Text] [PDF]