A novel bioluminescent mouse model and effective therapy for adult T-cell leukemia/lymphoma

Sherry T. Shu, Murali V P Nadella, Wessel P. Dirksen, Soledad A. Fernandez, Nanda K. Thudi, Jillian L. Werbeck, Michael Dale Lairmore, Thomas J. Rosol

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Adult T-cell /lymphomaleukemia (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Approximately 80% of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a life-threatening complication leading to a poor prognosis. Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1α (MIP-1α) are important factors in the pathogenesis of HHM in ATLL and the expression of PTHrP can be activated by nuclear factor κB (NF-κB). NF-κB is constitutively activated in ATLL cells and is essential for leukemogenesis including transformation of lymphocytes infected by HTLV-1. Our goal was to evaluate the effects of NF-κB disruption by a proteasomal inhibitor (PS-341) and osteoclastic inhibition by zoledronic acid (Zol) on the development of ATLL and HHM using a novel bioluminescent mouse model. We found that PS-341 decreased cell viability, increased apoptosis, and down-regulated PTHrP expression in ATLL cells in vitro. To investigate the in vivo efficacy, nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were xenografted with ATLL cells and treated with vehicle control, PS-341, Zol, or a combination of PS-341 and Zol. Bioluminescent imaging and tumor cell count showed a significant reduction in tumor burden in mice from all treatment groups. All treatments also significantly reduced the plasma calcium concentrations. Zol treatment increased trabecular bone volume and decreased osteoclast parameters. PS-341 reduced PTHrP and MIP-1α expression in tumor cells in vivo. Our results indicate that both PS-341 and Zol are effective treatments for ATLL and HHM, which are refractory to conventional therapy.

Original languageEnglish (US)
Pages (from-to)11859-11866
Number of pages8
JournalCancer Research
Volume67
Issue number24
DOIs
StatePublished - Dec 15 2007
Externally publishedYes

Fingerprint

Adult T Cell Leukemia Lymphoma
zoledronic acid
T-Lymphocytes
Parathyroid Hormone-Related Protein
Macrophage Inflammatory Proteins
Therapeutics
Human T-lymphotropic virus 1
SCID Mice
Osteoclasts
Lymphocyte Activation
Tumor Burden
Bortezomib
Neoplasms
Cell Survival
Cell Count
Apoptosis
Calcium

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Shu, S. T., Nadella, M. V. P., Dirksen, W. P., Fernandez, S. A., Thudi, N. K., Werbeck, J. L., ... Rosol, T. J. (2007). A novel bioluminescent mouse model and effective therapy for adult T-cell leukemia/lymphoma. Cancer Research, 67(24), 11859-11866. https://doi.org/10.1158/0008-5472.CAN-07-1701

A novel bioluminescent mouse model and effective therapy for adult T-cell leukemia/lymphoma. / Shu, Sherry T.; Nadella, Murali V P; Dirksen, Wessel P.; Fernandez, Soledad A.; Thudi, Nanda K.; Werbeck, Jillian L.; Lairmore, Michael Dale; Rosol, Thomas J.

In: Cancer Research, Vol. 67, No. 24, 15.12.2007, p. 11859-11866.

Research output: Contribution to journalArticle

Shu, ST, Nadella, MVP, Dirksen, WP, Fernandez, SA, Thudi, NK, Werbeck, JL, Lairmore, MD & Rosol, TJ 2007, 'A novel bioluminescent mouse model and effective therapy for adult T-cell leukemia/lymphoma', Cancer Research, vol. 67, no. 24, pp. 11859-11866. https://doi.org/10.1158/0008-5472.CAN-07-1701
Shu ST, Nadella MVP, Dirksen WP, Fernandez SA, Thudi NK, Werbeck JL et al. A novel bioluminescent mouse model and effective therapy for adult T-cell leukemia/lymphoma. Cancer Research. 2007 Dec 15;67(24):11859-11866. https://doi.org/10.1158/0008-5472.CAN-07-1701
Shu, Sherry T. ; Nadella, Murali V P ; Dirksen, Wessel P. ; Fernandez, Soledad A. ; Thudi, Nanda K. ; Werbeck, Jillian L. ; Lairmore, Michael Dale ; Rosol, Thomas J. / A novel bioluminescent mouse model and effective therapy for adult T-cell leukemia/lymphoma. In: Cancer Research. 2007 ; Vol. 67, No. 24. pp. 11859-11866.
@article{349e9c4b2753458193ad7767670503ef,
title = "A novel bioluminescent mouse model and effective therapy for adult T-cell leukemia/lymphoma",
abstract = "Adult T-cell /lymphomaleukemia (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Approximately 80{\%} of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a life-threatening complication leading to a poor prognosis. Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1α (MIP-1α) are important factors in the pathogenesis of HHM in ATLL and the expression of PTHrP can be activated by nuclear factor κB (NF-κB). NF-κB is constitutively activated in ATLL cells and is essential for leukemogenesis including transformation of lymphocytes infected by HTLV-1. Our goal was to evaluate the effects of NF-κB disruption by a proteasomal inhibitor (PS-341) and osteoclastic inhibition by zoledronic acid (Zol) on the development of ATLL and HHM using a novel bioluminescent mouse model. We found that PS-341 decreased cell viability, increased apoptosis, and down-regulated PTHrP expression in ATLL cells in vitro. To investigate the in vivo efficacy, nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were xenografted with ATLL cells and treated with vehicle control, PS-341, Zol, or a combination of PS-341 and Zol. Bioluminescent imaging and tumor cell count showed a significant reduction in tumor burden in mice from all treatment groups. All treatments also significantly reduced the plasma calcium concentrations. Zol treatment increased trabecular bone volume and decreased osteoclast parameters. PS-341 reduced PTHrP and MIP-1α expression in tumor cells in vivo. Our results indicate that both PS-341 and Zol are effective treatments for ATLL and HHM, which are refractory to conventional therapy.",
author = "Shu, {Sherry T.} and Nadella, {Murali V P} and Dirksen, {Wessel P.} and Fernandez, {Soledad A.} and Thudi, {Nanda K.} and Werbeck, {Jillian L.} and Lairmore, {Michael Dale} and Rosol, {Thomas J.}",
year = "2007",
month = "12",
day = "15",
doi = "10.1158/0008-5472.CAN-07-1701",
language = "English (US)",
volume = "67",
pages = "11859--11866",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "24",

}

TY - JOUR

T1 - A novel bioluminescent mouse model and effective therapy for adult T-cell leukemia/lymphoma

AU - Shu, Sherry T.

AU - Nadella, Murali V P

AU - Dirksen, Wessel P.

AU - Fernandez, Soledad A.

AU - Thudi, Nanda K.

AU - Werbeck, Jillian L.

AU - Lairmore, Michael Dale

AU - Rosol, Thomas J.

PY - 2007/12/15

Y1 - 2007/12/15

N2 - Adult T-cell /lymphomaleukemia (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Approximately 80% of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a life-threatening complication leading to a poor prognosis. Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1α (MIP-1α) are important factors in the pathogenesis of HHM in ATLL and the expression of PTHrP can be activated by nuclear factor κB (NF-κB). NF-κB is constitutively activated in ATLL cells and is essential for leukemogenesis including transformation of lymphocytes infected by HTLV-1. Our goal was to evaluate the effects of NF-κB disruption by a proteasomal inhibitor (PS-341) and osteoclastic inhibition by zoledronic acid (Zol) on the development of ATLL and HHM using a novel bioluminescent mouse model. We found that PS-341 decreased cell viability, increased apoptosis, and down-regulated PTHrP expression in ATLL cells in vitro. To investigate the in vivo efficacy, nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were xenografted with ATLL cells and treated with vehicle control, PS-341, Zol, or a combination of PS-341 and Zol. Bioluminescent imaging and tumor cell count showed a significant reduction in tumor burden in mice from all treatment groups. All treatments also significantly reduced the plasma calcium concentrations. Zol treatment increased trabecular bone volume and decreased osteoclast parameters. PS-341 reduced PTHrP and MIP-1α expression in tumor cells in vivo. Our results indicate that both PS-341 and Zol are effective treatments for ATLL and HHM, which are refractory to conventional therapy.

AB - Adult T-cell /lymphomaleukemia (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Approximately 80% of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a life-threatening complication leading to a poor prognosis. Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1α (MIP-1α) are important factors in the pathogenesis of HHM in ATLL and the expression of PTHrP can be activated by nuclear factor κB (NF-κB). NF-κB is constitutively activated in ATLL cells and is essential for leukemogenesis including transformation of lymphocytes infected by HTLV-1. Our goal was to evaluate the effects of NF-κB disruption by a proteasomal inhibitor (PS-341) and osteoclastic inhibition by zoledronic acid (Zol) on the development of ATLL and HHM using a novel bioluminescent mouse model. We found that PS-341 decreased cell viability, increased apoptosis, and down-regulated PTHrP expression in ATLL cells in vitro. To investigate the in vivo efficacy, nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were xenografted with ATLL cells and treated with vehicle control, PS-341, Zol, or a combination of PS-341 and Zol. Bioluminescent imaging and tumor cell count showed a significant reduction in tumor burden in mice from all treatment groups. All treatments also significantly reduced the plasma calcium concentrations. Zol treatment increased trabecular bone volume and decreased osteoclast parameters. PS-341 reduced PTHrP and MIP-1α expression in tumor cells in vivo. Our results indicate that both PS-341 and Zol are effective treatments for ATLL and HHM, which are refractory to conventional therapy.

UR - http://www.scopus.com/inward/record.url?scp=37549003696&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=37549003696&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-07-1701

DO - 10.1158/0008-5472.CAN-07-1701

M3 - Article

C2 - 18089816

AN - SCOPUS:37549003696

VL - 67

SP - 11859

EP - 11866

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 24

ER -