Loss of Socs2 improves molecular responses to IFNα in a mouse model of myeloproliferative neoplasms driven by JAK2-V617F

被引：0

作者：

Usart, Marc ^{[1
,2
,3
]}

Kimmerlin, Quentin ^{[1
,2
,3
]}

Stetka, Jan ^{[1
,2
]}

Stoll, Cedric ^{[1
,2
]}

Rai, Shivam ^{[1
,2
]}

Fonseca, Tiago Almeida ^{[1
,2
]}

Karjalainen, Riikka ^{[1
,2
]}

Hao-Shen, Hui ^{[1
,2
]}

Roux, Julien ^{[4
,5
,6
]}

El Taher, Athimed ^{[4
,5
,6
]}

Lynch, Dylan ^{[7
]}

Makukhin, Nikolai ^{[7
]}

Ciulli, Alessio ^{[7
]}

Skoda, Radek C. ^{[1
,2
,3
]}

机构：

[1] Univ Basel, Dept Biomed, Expt Hematol, Basel, Switzerland

[2] Univ Basel, Basel, Switzerland

[3] Baylor Coll Med, Dan Duncan Comprehens Canc Ctr, Houston, TX USA

[4] Univ Basel, Dept Biomed, Bioinformat, Basel, Switzerland

[5] Univ Hosp Basel, Basel, Switzerland

[6] Swiss Inst Bioinformat, Basel, Switzerland

[7] Univ Dundee, Ctr Targeted Prot Degradat, Sch Life Sci, 1 James Lindsay Pl, Dundee DD1 5JJ, Scotland

来源：

LEUKEMIA | 2025年

基金：

瑞士国家科学基金会;

关键词：

HEMATOPOIETIC STEM-CELLS; INTERFERON-ALPHA; EXPRESSION; PROLIFERATION; DISEASE; FATE;

D O I：

10.1038/s41375-025-02550-5

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Therapy with pegylated interferon alpha (pegIFN alpha) can induce a deep molecular response in a subset of patients with myeloproliferative neoplasms (MPN). Here we investigated the role of Socs2, a negative regulator of cytokine signaling, in modulating the response to pegIFN alpha in a JAK2-V617F mouse model of MPN. Deleting Socs2 in JAK2-V617F mice resulted in increased sensitivity to cytokines, without causing significant alterations in the MPN phenotype. When subjected to pegIFN alpha, the loss of Socs2 enhanced the depletion of JAK2-mutant hematopoietic stem cells (HSCs), evidenced by reduced chimerism in peripheral blood and bone marrow compared to vehicle controls. Additionally, pegIFN alpha-treated Socs2-deficient JAK2-mutant HSCs exhibited functional impairments in secondary transplantations, reflecting long-term detrimental decline of their stemness. These findings demonstrate that loss of Socs2 enhances the effectiveness of pegIFN alpha in depleting the JAK2-mutant HSC clone. In line with the genetic ablation of Socs2, the SOCS2 inhibitor MN714 combined with IFN alpha exhibited better efficacy than IFN alpha alone in reducing the output of CD34+ cells from PV patients in vitro. Targeting SOCS2 could therefore improve therapeutic responsiveness in MPN patients receiving interferon therapy.

引用

页码：876 / 887

页数：12

共 38 条

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