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CANCER STEM CELLS

Human T-Cell Lymphotropic Virus Type 1 Infection of CD34⁺ Hematopoietic Progenitor Cells Induces Cell Cycle Arrest by Modulation of p21^cip1/waf1 and Survivin

^aDepartment of Microbiology and Immunology and
^bCenter for Humanized SCID Mouse Models, State University of New York Upstate Medical University, Syracuse, New York, USA

Key Words. Cell cycle heterogeneity • Leukemia • Lentiviral vectors • Stem/progenitor cell • Viral persistence

Correspondence: Correspondence: Gerold Feuer, Ph.D., Department of Microbiology and Immunology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, New York 13210, USA. Telephone: 315-464-7681; Fax: 315-464-4417; e-mail: feuerg{at}upstate.edu

Received on April 15, 2008; accepted for publication on September 14, 2008.

First published online in STEM CELLS EXPRESS  September 25, 2008.

Human T-cell lymphotropic virus type 1 (HTLV-1) is an oncogenic retrovirus and the etiologic agent of adult T-cell leukemia (ATL), an aggressive CD4⁺ malignancy. HTLV-2 is highly homologous to HTLV-1; however, infection with HTLV-2 has not been associated with lymphoproliferative diseases. Although HTLV-1 infection of CD4⁺ lymphocytes induces cellular replication and transformation, infection of CD34⁺ human hematopoietic progenitor cells (HPCs) strikingly results in G₀/G₁ cell cycle arrest and suppression of in vitro clonogenic colony formation by induction of expression of the cdk inhibitor p21^cip1/waf1 (p21) and concurrent repression of survivin. Immature CD34⁺/CD38^– hematopoietic stem cells (HSCs) were more susceptible to alterations of p21 and survivin expression as a result of HTLV-1 infection, in contrast to more mature CD34⁺/CD38⁺ HPCs. Knockdown of p21 expression in HTLV-1-infected CD34⁺ HPCs partially abrogated cell cycle arrest. Notably, HTLV-2, an HTLV strain that is not associated with leukemogenesis, does not significantly modulate p21 and survivin expression and does not suppress hematopoiesis from CD34⁺ HPCs in vitro. We speculate that the remarkable differences in the activities displayed by CD34⁺ HPCs following infection with HTLV-1 or HTLV-2 suggest that HTLV-1 uniquely exploits cell cycle arrest mechanisms to establish a latent infection in hematopoietic progenitor/hematopoietic stem cells and initiates preleukemic events in these cells, which eventually results in the manifestation of ATL.

Disclosure of potential conflicts of interest is found at the end of this article.