Distinct effects of ruxolitinib and interferon-alpha on murine JAK2V617F myeloproliferative neoplasm hematopoietic stem cell populations

被引：39

作者：

Austin, Rebecca J. ^{[1
,2
]}

Straube, Jasmin ^{[1
]}

Bruedigam, Claudia ^{[1
]}

Pali, Gabor ^{[1
]}

Jacquelin, Sebastien ^{[1
]}

Vu, Therese ^{[1
]}

Green, Joanne ^{[1
]}

Graesel, Julius ^{[3
]}

Lansink, Lianne ^{[1
]}

Cooper, Leanne ^{[1
]}

Lee, Shin-Jye ^{[4
]}

Chen, Nien-Tsu ^{[4
]}

Lee, Chung-Wei ^{[5
]}

Haque, Ashraful ^{[1
]}

Heidel, Florian H. ^{[6
,7
]}

D'Andrea, Richard ^{[8
,9
]}

Hill, Geoff R. ^{[1
,12
]}

Mullally, Ann ^{[10
]}

Milsom, Michael D. ^{[3
]}

Bywater, Megan ^{[1
,2
]}

Lane, Steven W. ^{[1
,2
,11
]}

机构：

[1] QIMR Berghofer Med Res Inst, Canc Program, 300 Herston Rd, Brisbane, Qld 3006, Australia

[2] Univ Queensland, St Lucia, Qld 4072, Australia

[3] Heidelberg Inst Stem Cell Technol & Expt Med gGmb, D-69120 Heidelberg, Germany

[4] PharmaEssentia Co, Taipei, Taiwan

[5] PharmaEssentia USA LLC, Burlington, MA USA

[6] FLI, Leibniz Inst Aging, Beutenbergstr 11, D-07745 Jena, Germany

[7] Univ Klinikum Jena, Innere Med Hamatol & Onkol 2, D-07747 Jena, Germany

[8] Univ South Australia, Ctr Canc Biol, Adelaide, SA, Australia

[9] SA Pathol, Adelaide, SA, Australia

[10] Harvard Med Sch, Brigham & Womens Hosp, Div Hematol, Dept Med, Boston, MA 02115 USA

[11] Royal Brisbane & Womens Hosp, Canc Care Serv, Cnr Butterfield St & Bowen Bridge Rd, Herston, Qld 4029, Australia

[12] Seattle Canc Care Alliance, Fred Hutchinson Canc Ctr, Seattle, WA USA

来源：

LEUKEMIA | 2020年 / 34卷 / 04期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

TYROSINE KINASE JAK2; POLYCYTHEMIA-VERA; MOLECULAR RESPONSES; REPLICATION STRESS; AVAILABLE THERAPY; ALLELE BURDEN; SELF-RENEWAL; MOUSE MODEL; MUTATION; ACTIVATION;

D O I：

10.1038/s41375-019-0638-y

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

JAK2V617F is the most common mutation in patients with BCR-ABL negative myeloproliferative neoplasms (MPNs). The eradication of JAK2V617F hematopoietic stem cells (HSCs) is critical for achieving molecular remissions and cure. We investigate the distinct effects of two therapies, ruxolitinib (JAK1/2 inhibitor) and interferon-alpha (IFN-alpha), on the disease-initiating HSC population. Whereas ruxolitinib inhibits Stat5 activation in erythroid progenitor populations, it fails to inhibit this same pathway in HSCs. In contrast, IFN-alpha has direct effects on HSCs. Furthermore, STAT1 phosphorylation and pathway activation is greater after IFN-alpha stimulation in Jak2V617F murine HSCs with increased induction of reactive oxygen species, DNA damage and reduction in quiescence after chronic IFN-alpha treatment. Interestingly, ruxolitinib does not block IFN-alpha induced reactive oxygen species and DNA damage in Jak2V617F murine HSCs in vivo. This work provides a mechanistic rationale informing how pegylated IFN-alpha reduces JAK2V617F allelic burden in the clinical setting and may inform future clinical efforts to combine ruxolitinib with pegylated IFN-alpha in patients with MPN.

引用

页码：1075 / 1089

页数：15

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