Molecular approach to human leukemia: isolation and characterization of the first human retrovirus HTLV-1 and its impact on tumorigenesis in adult T-cell leukemia

Abstract

Molecular biology of mouse and chicken retroviruses had identified oncogenes and provided a revolutionary concept in understanding of cancers. A human retrovirus was established during 1980-1982 in linkage with a unique human leukemia, concurrently in Japan and USA. This review covers our efforts on the discovery of new retrovirus, Human T-cell Leukemia Virus Type 1 (HTLV-1), first introducing to a new class of retroviruses with a unique regulatory factors, Tax and Rex. Then it is followed by analyses of molecular interaction of the vial Tax with cellular machineries involved in the pathogenesis of Adult T-cell Leukemia (ATL). And then a probable mechanism of pathogenesis of ATL is proposed including recent findings on HBZ after our efforts.

Fig. 1

Identification of HTLV-1 in a cell line MT-2. (A) Reverse transcriptase activity. Concentrated culture fluid of MT-2 cells was centrifuged on a gradient of 20–60% sucrose and the fractions were assayed for DNA polymerase activity with poly(A)-oligo(dT) (●), no exogenous template (▲), or in presence of MnCl₂ instead of MgCl₂ (♦). △ (or open triangle) represents the density of each fraction. (B) Detection of provirus sequences by Southern blot analysis of cellular DNA of ATL-related MT-1 (a) and MT-2 (b), ATL-unrelated A204 (c) and KB cells (d). Cellular DNA was digested with Eco-R1 and probed with cDNA prepared by the endogenous reaction of active fractions in Fig. 1(A).

Fig. 2

Illustration of the HTLV-1 genome structure, gene expression and function of Tax. In upper half, transient expression by a combination of Tax and Rex is summarized, and in lower half, direct targets of Tax and their effects on cellular functions are summarized. In the lower, open arrows represent “enhancement” and closed arrows “down-regulation”, some arrows with major player in the pathway.

Fig. 3

Mode of Tax functions. Typical examples are (a) transcriptional trans-activation with CREB, NF-kB or SRF, (b) transcriptional trans-repression with p53 or E47, and (c) promotion of cells from G1 toward S phase of cell cycle through inhibition of tumor suppressor proteins p16ink4 and p15ink4. Closed circle: histone; Ac: Acetyl residue.

Fig. 4

Probable mechanism of pathogenesis in ATL. Circles with X⁺ represents Tax expressing T cell and those with X⁻ represents Tax expression negative infected T cell. CTL represents cytotoxic T cell against virus expressing cells and dotted circle represents infected cell injured.

Fig. 5

Illustration of HBZ expression and the functions.