Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling

Chen, Edwin; Beer, Philip A.; Godfrey, Anna L.; Ortmann, Christina A.; Li, Juan; Costa-Pereira, Ana P.; Ingle, Catherine E.; Dermitzakis, Emmanouil; Campbell, Peter J.; Green, Anthony R.

doi:10.1016/j.ccr.2010.10.013

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Title		Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling
Authors		Chen, Edwin Beer, Philip A. Godfrey, Anna L. Ortmann, Christina A. Li, Juan Costa-Pereira, Ana P. Ingle, Catherine E. Dermitzakis, Emmanouil Campbell, Peter J. Green, Anthony R. show all authors [1 - 10]
Published in		Cancer Cell. 2010, vol. 18, no. 5, p. 524-535
Abstract		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.
Keywords		Amino Acid Substitution — Cell Culture Techniques — Cell Differentiation/genetics — Cells, Cultured — Cluster Analysis — Down-Regulation — Gene Expression Profiling — Gene Expression Regulation, Neoplastic — Heterozygote — Humans — Interferons/metabolism — Janus Kinase 2/genetics — Megakaryocytes/pathology — Myeloproliferative Disorders/genetics — Phenotype — Phosphorylation — Polycythemia Vera/genetics — STAT1 Transcription Factor/genetics/metabolism — STAT5 Transcription Factor/genetics/metabolism — Signal Transduction — Thrombocythemia, Essential/*genetics — Transcriptional Activation
Identifiers		DOI: 10.1016/j.ccr.2010.10.013 PMID: 21074499
Full text		Article (Accepted version) - Free access Other version: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2996868/pdf/ukmss-33568.pdf
Structures		Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement
Research group		Population Genomics and Genetics of Complex Traits (892)
Citation (ISO format)		CHEN, Edwin et al. Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling. In: Cancer Cell, 2010, vol. 18, n° 5, p. 524-535. doi: 10.1016/j.ccr.2010.10.013 https://archive-ouverte.unige.ch/unige:20617