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.
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 G(0)/G(1) 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.
Banerjee
Prabal
P
Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.
Sieburg
Michelle
M
Samuelson
Elizabeth
E
Feuer
Gerold
G
D018952:Antigens, CD34 / Q000378:metabolism*; D002453:Cell Cycle; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic; D016355:Genes, pX; D015490:HTLV-I Infections / Q000821:virology; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000821:virology*; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D016086:Lentivirus / Q000235:genetics; D008232:Lymphoproliferative Disorders / Q000378:metabolism* / Q000821:virology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D000077022:Survivin; D014162:Transfection; D014759:Viral Envelope Proteins / Q000378:metabolism
D018952:Antigens, CD34; C107489:BIRC5 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C028391:G protein, vesicular stomatitis virus; D051034:Inhibitor of Apoptosis Proteins; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D014759:Viral Envelope Proteins