Hepatic thrombopoietin gene silencing reduces platelet count and breast cancer progression in transgenic MMTV-PyMT mice

Toshiaki Shirai, Alexey S. Revenko, Justin Tibbitts, Anh T.P. Ngo, Annachiara Mitrugno, Laura D. Healy, Jennifer Johnson, Erik I. Tucker, Monica T. Hinds, Lisa M. Coussens, Owen J.T. McCarty, Brett P. Monia, András Gruber

Research output: Contribution to journalArticle

Abstract

In humans, platelet count within the normal range is required for physiological hemostasis, but, adversely, platelets also support pathological thrombosis. Moreover, by releasing growth factors, they may enhance neoplastic proliferation. We hypothesize that platelet count correlates with platelet-dependent pathologies, even within the range of hemostatic competence. Because platelet production is promoted by thrombopoietin signaling through the myeloproliferative leukemia virus oncogene (cMPL), a receptor expressed on megakaryocytes, we evaluated the feasibility of selective targeting of hepatic thrombopoietin production to test this hypothesis. We synthesized murine- and primate-specific antisense oligonucleotides (THPO-ASO) that silence hepatic thrombopoietin gene (THPO) expression without blocking extrahepatic THPO. Repeated doses of THPO-ASO were administered to mice and a baboon, causing a sustained 50% decline in plasma thrombopoietin levels and platelet count within 4 weeks in both species. To investigate whether reducing platelet count within the translationally relevant hemostatic range could alter a neoplastic process, we administered THPO-ASO to 6-week-old transgenic MMTV-PyMT mice that develop early ductal atypia that progresses into cMPL-negative fatal metastatic breast cancer within 2 to 3 months. THPO-ASO treatment increased the average time to euthanasia (primary humane endpoint) at 2 cm3 combined palpable tumor volume. Our results show that THPO-ASO reduced blood platelet count, plasma platelet factor 4, vascular endothelial growth factor, thrombopoietin levels, bone marrow megakaryocyte density, tumor growth rate, proliferation index, vascularization, platelet and macrophage content, and pulmonary metastases vs untreated controls. These findings confirm that sustained and moderate pharmacological platelet count reduction is feasible with THPO-ASO administration and can delay progression of certain platelet-dependent pathological processes within a safe hemostatic platelet count range.

Original languageEnglish (US)
Pages (from-to)3080-3091
Number of pages12
JournalBlood Advances
Volume3
Issue number20
DOIs
StatePublished - Oct 22 2019

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Thrombopoietin
Gene Silencing
Platelet Count
Breast Neoplasms
Liver
Blood Platelets
Genes
Hemostatics
Megakaryocytes
Platelet Factor 4
Neoplastic Processes
Euthanasia
Papio
Antisense Oligonucleotides
Alveolar Macrophages
Pathologic Processes
Tumor Burden
Hemostasis
Oncogenes
Mental Competency

ASJC Scopus subject areas

  • Hematology

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Hepatic thrombopoietin gene silencing reduces platelet count and breast cancer progression in transgenic MMTV-PyMT mice. / Shirai, Toshiaki; Revenko, Alexey S.; Tibbitts, Justin; Ngo, Anh T.P.; Mitrugno, Annachiara; Healy, Laura D.; Johnson, Jennifer; Tucker, Erik I.; Hinds, Monica T.; Coussens, Lisa M.; McCarty, Owen J.T.; Monia, Brett P.; Gruber, András.

In: Blood Advances, Vol. 3, No. 20, 22.10.2019, p. 3080-3091.

Research output: Contribution to journalArticle

Shirai, Toshiaki ; Revenko, Alexey S. ; Tibbitts, Justin ; Ngo, Anh T.P. ; Mitrugno, Annachiara ; Healy, Laura D. ; Johnson, Jennifer ; Tucker, Erik I. ; Hinds, Monica T. ; Coussens, Lisa M. ; McCarty, Owen J.T. ; Monia, Brett P. ; Gruber, András. / Hepatic thrombopoietin gene silencing reduces platelet count and breast cancer progression in transgenic MMTV-PyMT mice. In: Blood Advances. 2019 ; Vol. 3, No. 20. pp. 3080-3091.
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AU - Mitrugno, Annachiara

AU - Healy, Laura D.

AU - Johnson, Jennifer

AU - Tucker, Erik I.

AU - Hinds, Monica T.

AU - Coussens, Lisa M.

AU - McCarty, Owen J.T.

AU - Monia, Brett P.

AU - Gruber, András

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