HTLV-1 viral oncogene HBZ induces osteolytic bone disease in transgenic mice

Abstract

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T cell malignancy that occurs in HTLV-1 infected patients. Most ATL patients develop osteolytic lesions and hypercalcemia of malignancy, causing severe skeletal related complications and reduced overall survival. The HTLV-1 virus encodes 2 viral oncogenes, Tax and HBZ. Tax, a transcriptional activator, is critical to ATL development, and has been implicated in pathologic osteolysis. HBZ, HTLV-1 basic leucine zipper transcription factor, promotes tumor cell proliferation and disrupts Wnt pathway modulators; however, its role in ATL induced osteolytic bone loss is unknown. To determine if HBZ is sufficient for the development of bone loss, we established a transgenic Granzyme B HBZ (Gzmb-HBZ) mouse model. Lymphoproliferative disease including tumors, enlarged spleens and/or abnormal white cell counts developed in two-thirds of Gzmb-HBZ mice at 18 months. HBZ positive cells were detected in tumors, spleen and bone marrow. Importantly, pathologic bone loss and hypercalcemia were present at 18 months. Bone-acting factors were present in serum and RANKL, PTHrP and DKK1, key mediators of hypercalcemia and bone loss, were upregulated in Gzmb-HBZ T cells. These data demonstrate that Gzmb-HBZ mice model ATL bone disease and express factors that are current therapeutic targets for metastatic and bone resident tumors.

HTLV-1 viral oncogene HBZ drives bone destruction in adult T cell leukemia

“…(D and E) Scatter plots of the correlation (as indicated by linear best fit curve) between osteoclast surface/ bone surface or osteoclast number/bone surface on the y axis vs. percentage of human CD4 + T cells in the peripheral blood. P value (Pearson correlation coefficient test was adopted to determine statistically significant correlation between the 2 groups) is shown; ns, P > 0.05. expression) (19). To confirm these results, we used the inducible Tet-on Tax1 expression in Jurkat cells (35).…”

“…In contrast to Tax loss over time, HBZ is consistently expressed throughout ATL development and progression (11). HBZ expression has also been shown to modulate osteoblast regulators such as DKK1 and Wnt5a (43,44), and we recently reported that aged Gzmb-HBZ transgenic mice develop LPD associated with bone loss and hypercalcemia (19). These data suggest that Tax and HBZ can independently regulate bone-acting factors and could contribute to disease-associated bone loss.…”

“…We recently demonstrated that Gzmb-HBZ transgenic mice develop lymphoproliferative disease (LPD), splenomegaly, and osteolytic disease after an 18-month latency. These mice also exhibit elevated levels of inflammatory and bone-activating factors such as IL-6, IL-3, and MCP-1 (19), indicating that HBZ may also contribute to ATL-associated bone pathology. Despite these findings, the precise mechanism for how HBZ contributes to lymphoproliferative and bone disease in the context of ATL remains unclear.…”

Strategies of Human T-Cell Leukemia Virus Type 1 for Persistent Infection: Implications for Leukemogenesis of Adult T-Cell Leukemia-Lymphoma

“…In HBZ-Tg mice, production of the immunosuppressive cytokine IL-10 is higher than in wild-type littermates, suggesting that HBZ contributes to the suppression of host immunity (Yasuma et al, 2016). Another transgenic mouse strain that expresses HBZ under the control of the granzyme B promoter demonstrates a lymphoproliferative disease and hypercalcemia, which is often seen in ATL patients (Esser et al, 2017). HBZ dysregulates the transcription of many cellular genes using its two different molecular forms, HBZ protein and HBZ RNA (Satou et al, 2006;Mitobe et al, 2015).…”

Mouse Models That Enhanced Our Understanding of Adult T Cell Leukemia

“…More recently, a transgenic HBZ mouse model using Granzyme B (Gzmb- HBZ ) was generated ( Esser et al, 2017 ). In addition to splenomegaly, abnormal white cell count, tumors developing after 18 months, in two thirds of the Gzmb- HBZ mice, as well as pathologic bone loss and hypercalcaemia were obtained ( Kinosada et al, 2017 ) ( Table 1 ).…”