“Tax-ing” the cancer stem cell

A transgenic mouse model of the HTLV-1 Tax gene generates T-cell lymphomas characteristic of ATLL. In this issue of Blood, Yamazaki and colleagues describe the identification of cancer stem cells in Tax-transgenic mice that develop lymphoma, which has implications for the origins of ATLL in HTLV-1–infected patients.

Infection with the human oncogenic retrovirus human T-cell leukemia virus type-1 (HTLV-1) is etiologically associated with development of adult T-cell leukemia/lymphoma (ATLL). Neonatal or perinatal transmission of HTLV-1 results in the development of ATLL, generally manifesting as a monoclonal expansion of CD4⁺CD25⁺ T cells, although case reports have also described lymphoproliferative malignancies that display more immature cellular phenotypes. The HTLV-1 Tax oncoprotein is a relatively promiscuous transactivator of both viral and cellular gene transcription and is linked closely to the initiation of leukemogenesis. Transgenic mice constructed to target expression of HTLV-1 Tax to the mature T-cell lineage using a LCK promoter reproducibly develop immature and mature T-cell leukemia-lymphomas, with immunologic and pathologic similarities to human forms of ATLL.^1,2  In the current study by Yamazaki et al, splenic lymphomatous cells were harvested and purified from Tax-transgenic mice using a combination of immunologic and physiologic markers for cancer stem cells (CSCs) and were injected into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice using a limiting-dilution analysis.³  Injection with as few as 10² CSCs was sufficient to recapitulate the original lymphoma and reestablish CSCs in recipient SCID mice, implicating a role for leukemic stem cells in this hematolymphoid malignancy.

Leukemia CSCs have the ability to self-renew, are sequestered in the bone marrow microenvironment, and are relatively resistant to conventional chemotherapeutic treatment regimens. The recent focus and characterization of the role of CSCs in the induction of acute myeloid leukemia (AML) has generated a paradigm for cancers caused by CSCs and has resulted in reevaluation of therapeutic strategies for successfully targeting the elimination of these leukemias in patients.⁴  Although the Tax-transgenic mouse model is not a perfect representative of ATLL manifestation in humans, the results presented in this issue of Blood are particularly intriguing because other investigators have suggested that HTLV-1 infection in the human bone marrow, and in human hematopoietic progenitor/stem cells (HP/HSCs) specifically, may facilitate the early events initiating ATLL development.⁵  As mentioned, ATLL manifests primarily in persons infected at birth; infection later in life is associated with the neurologic disorder HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which arises in a minority of seropositive patients.⁶  Notably, HTLV-1 has previously been shown to productively infect human CD34⁺ HP/HSCs and induce cell-cycle arrest. This is in stark contrast to immortalization and transformation associated with HTLV-1 infection of mature T cells.^7,8  Because a limited number of ATLL cases display phenotypes indicative of immature hematopoietic cells, HTLV-1 infection and transformation of hematopoietic progenitor or stem cells in humans may result in the generation of virally infected ATLL CSCs.⁹  Indeed, lymphoma cells and CSCs from Tax-transgenic mice were also demonstrated to sequester in the osteoblastic and vascular niches of the bone marrow in transplanted SCID mice. It is interesting to speculate that if ATLL in patients arises from a CSC, the sequestration of HTLV-1–infected HP/HSCs in the bone marrow microenvironment may be a contributing factor in the resistance of this leukemia to treatment with conventional chemo-therapies.

It is important to keep in mind the limitations in the interpretation of data derived from all transgenic mouse models. Preferentially targeting the overexpression of the Tax oncoprotein in maturing T cells most likely is not reflective of the interactions of HTLV-1 with various target cells in vivo. It also does not account for the role of the viral accessory genes, such as HBZ, in ultimately modulating viral leukemogenesis. It remains to be determined whether results from the Tax-transgenic model are truly illustrative of the human disease. However, this murine model provides interesting clues into the mechanisms of HTLV-1 pathogenesis, and this may eventually group ATLL along with hematologic malignancies that have a CSC origin. It would be a dramatic development if oncogenic viruses such as HTLV-1 exploit and target the infection of hematopoietic stem cells to establish bone marrow resident CSCs.