Distinct Clinical Phenotypes Associated with JAK2V617F Reflect Differential STAT1 Signaling

被引：139

作者：

Chen, Edwin ^{[1
,2
]}

Beer, Philip A. ^{[1
,2
,3
]}

Godfrey, Anna L. ^{[1
,2
,3
]}

Ortmann, Christina A. ^{[1
,2
,3
]}

Li, Juan ^{[1
,2
]}

Costa-Pereira, Ana P. ^{[4
]}

Ingle, Catherine E. ^{[5
]}

Dermitzakis, Emmanouil T. ^{[5
]}

Campbell, Peter J. ^{[5
]}

Green, Anthony R. ^{[1
,2
,3
]}

机构：

[1] Univ Cambridge, Cambridge Inst Med Res, Cambridge CB2 0XY, England

[2] Univ Cambridge, Dept Haematol, Cambridge CB2 0XY, England

[3] Addenbrookes Hosp, Dept Haematol, Cambridge CB2 0XY, England

[4] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Surg & Canc, London W12 0NN, England

[5] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

来源：

CANCER CELL | 2010年 / 18卷 / 05期

关键词：

HEMATOPOIETIC STEM-CELLS; V617F MUTATION OCCURS; TYROSINE KINASE JAK2; POLYCYTHEMIA-VERA; GENE-EXPRESSION; ESSENTIAL THROMBOCYTHEMIA; CYTOKINE RECEPTOR; MYELOPROLIFERATIVE DISORDERS; ACTIVATION; PHOSPHORYLATION;

D O I：

10.1016/j.ccr.2010.10.013

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The JAK2V617F mutation is associated with distinct myeloproliferative neoplasms, including polycythemia vera (PV) and essential thrombocythemia (ET), but it remains unclear how it generates disparate disorders. By comparing clonally-derived mutant and wild-type cells from individual patients, we demonstrate that the transcriptional consequences of JAK2V617F are subtle, and that JAK2V617F-heterozygous erythroid cells from ET and PV patients exhibit differential interferon signaling and STAT1 phosphorylation. Increased STAT1 activity in normal CD34-positive progenitors produces an ET-like phenotype, whereas downregulation of STAT1 activity in JAK2V617F-heterozygous ET progenitors produces a PV-like phenotype. Our results illustrate the power of clonal analysis, indicate that the consequences of JAK2V617F reflect a balance between STAT5 and STAT1 activation and are relevant for other neoplasms associated with signaling pathway mutations.

引用

页码：524 / 535

页数：12

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