Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-alpha in a murine model of polycythemia vera

Mullally, Ann, Bruedigam, Claudia, Poveromo, Luke, Heidel, Florian H., Purdon, Amy, Vu, Therese, Austin, Rebecca, Heckl, Dirk, Breyfogle, Lawrence J., Kuhn, Catherine Paine, Kalaitzidis, Demetrios, Armstrong, Scott A., Williams, David A., Hill, Geoff R., Ebert, Benjamin L. and Lane, Steven W. (2013) Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-alpha in a murine model of polycythemia vera. Blood, 121 18: 3692-3702. doi:10.1182/blood-2012-05-432989


Author Mullally, Ann
Bruedigam, Claudia
Poveromo, Luke
Heidel, Florian H.
Purdon, Amy
Vu, Therese
Austin, Rebecca
Heckl, Dirk
Breyfogle, Lawrence J.
Kuhn, Catherine Paine
Kalaitzidis, Demetrios
Armstrong, Scott A.
Williams, David A.
Hill, Geoff R.
Ebert, Benjamin L.
Lane, Steven W.
Title Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-alpha in a murine model of polycythemia vera
Formatted title
Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-α in a murine model of polycythemia vera
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
1528-0020
Publication date 2013-05-01
Year available 2013
Sub-type Article (original research)
DOI 10.1182/blood-2012-05-432989
Open Access Status DOI
Volume 121
Issue 18
Start page 3692
End page 3702
Total pages 11
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Language eng
Abstract Interferon-α (IFNα) is an effective treatment of patients with myeloproliferative neoplasms (MPNs). In addition to inducing hematological responses in most MPN patients, IFNα reduces the JAK2V617F allelic burden and can render the JAK2V617F mutant clone undetectable in some patients. The precise mechanism underlying these responses is incompletely understood and whether the molecular responses that are seen occur due to the effects of IFNα on JAK2V617F mutant stem cells is debated. Using a murine model of Jak2V617F MPN, we investigated the effects of IFNα on Jak2V617F MPN-propagating stem cells in vivo. We report that IFNα treatment induces hematological responses in the model and causes depletion of Jak2V617F MPN-propagating cells over time, impairing disease transplantation. We demonstrate that IFNα treatment induces cell cycle activation of Jak2V617F mutant long-term hematopoietic stem cells and promotes a predetermined erythroid-lineage differentiation program. These findings provide insights into the differential effects of IFNα on Jak2V617F mutant and normal hematopoiesis and suggest that IFNα achieves molecular remissions in MPN patients through its effects on MPN stem cells. Furthermore, these results support combinatorial therapeutic approaches in MPN by concurrently depleting dormant JAK2V617F MPN-propagating stem cells with IFNα and targeting the proliferating downstream progeny with JAK2 inhibitors or cytotoxic chemotherapy.
Keyword Chronic myeloid leukemia
V617F mutation occurs
Tyrosine kinase Jak2
Long-term treatment
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID P01 CA108631
K08 HL109734
DKH D/08/00661
K01DK092300
1026594
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
 
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