There is little doubt that HTLV-1 infection of T lymphocytes is necessary for leukemogenesis, but the molecular mechanisms of transformation are not certain. In contrast to several murine retroviruses, HTLV-1 does not contain an oncogene, and no consistent pattern of proviral integration next to a proto-oncogene has been discovered. In leukemic cells, however, viral integration shows a clonal pattern. In other words, although the site of viral integration in host chromosomes is random (the viral DNA is found at different locations in different cancers), the site of integration is identical within all cells of a given cancer. This would not occur if HTLV-1 were merely a passenger that infects cells after transformation; rather, it means that HTLV-1 must have been present at the moment of transformation, placing it at the “scene of the crime.” http://ebooksmedicine.net
The HTLV-1 genome contains the gag, pol, env, and long-terminal-repeat regions typical of all retroviruses, but, in contrast to other leukemia viruses, it contains another gene referred to as tax. Several aspects of HTLV-1’s transforming activity are attributable to Tax, the protein product of the tax gene. Tax is essential for viral replication, because it stimulates transcription of viral RNA from the 5′ long-terminal repeat. However, Tax also alters the transcription of several host cell genes and interacts with certain host cell signaling proteins. By doing so, Tax contributes to the acquisition of several cancer hallmarks, including the following:
Increased survival and growth of infected cells. Tax appears to interact with PI3 kinase and thereby stimulate the downstream signaling cascade, which you will recall promotes both cell survival and metabolic alterations that enhance cell growth. Tax also upregulates the expression of cyclin D and represses the expression of multiple CDK inhibitors, changes that promote cell cycle progression. Finally, Tax can activate the transcription factor NF-κB, which promotes the survival of many cell types, including lymphocytes.
Increased genomic instability. Tax may also cause genomic instability by interfering with DNA-repair functions and inhibiting cell cycle checkpoints activated by DNA damage. In line with these defects, HTLV-1–associated leukemias tend to be highly aneuploid.
The precise steps that lead to the development of adult T-cell leukemia/lymphoma are still not known, but a plausible scenario is as follows. Infection by HTLV-1 causes the expansion of a nonmalignant polyclonal cell population through stimulatory effects of Tax on cell proliferation. The proliferating T cells are at increased risk for mutations and genomic instability due to the effects of Tax and possibly other viral factors as well. This instability allows the accumulation of oncogenic mutations and eventually a monoclonal neoplastic T-cell population emerges. The most common driver mutations identified thus far are predicted to enhance T cell receptor signaling and stimulate NF-κB activation.
HTLV-1causesaTcellleukemiathatisendemicinJapanandtheCaribbean.
TheHTLV-1genomeencodesaviralproteincalledTax, whichstimulatesproliferation,enhancescellsurvival,andinterfereswithcellcyclecontrols.Althoughthisproliferationinitiallyispolyclonal,theproliferatingTcellsareatincreasedriskforsecondarymutationsthatmayleadtotheoutgrowthofamonoclonalleukemia.
Fig. 6.33 TransformingeffectsofHPVE6andE7proteins.TheneteffectofHPVE6andE7proteinsistoimmortalizecellsandremovetherestraintsoncellproliferation.