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Activating JAK2 mutants reveal cytokine receptor coupling differences that impact outcomes in myeloproliferative neoplasm
- Source :
- Leukemia
- Publication Year :
- 2017
- Publisher :
- Springer Science and Business Media LLC, 2017.
-
Abstract
- Janus tyrosine kinase 2 (JAK2) mediates downstream signaling of cytokine receptors in all hematological lineages, yet constitutively active JAK2 mutants are able to drive selective expansion of particular lineage(s) in myeloproliferative neoplasm (MPN). The molecular basis of lineage specificity is unclear. Here, we show that three activating JAK2 mutants with similar kinase activities in vitro elicit distinctive MPN phenotypes in mice by differentially expanding erythroid vs granulocytic precursors. Molecularly, this reflects the differential binding of JAK2 mutants to cytokine receptors EpoR and GCSFR in the erythroid vs granulocytic lineage and the creation of unique receptor/JAK2 complexes that generate qualitatively distinct downstream signals. Our results demonstrate that activating JAK2 mutants can differentially couple to selective cytokine receptors and change the signaling repertoire, revealing the molecular basis for phenotypic differences elicited by JAK2 (V617F) or mutations in exon 12. On the basis of these findings, receptor-JAK2 interactions could represent new targets of lineage-specific therapeutic approaches against MPN, which may be applicable to other cancers with aberrant JAK-STAT signaling.
- Subjects :
- 0301 basic medicine
Cancer Research
Lineage (genetic)
Recombinant Fusion Proteins
Mutation, Missense
Biology
medicine.disease_cause
Article
Cell Line
Mice
03 medical and health sciences
Genes, Reporter
Transduction, Genetic
hemic and lymphatic diseases
Protein Interaction Mapping
Receptors, Erythropoietin
medicine
Animals
Humans
Point Mutation
Cell Lineage
Erythropoiesis
Receptor
Tumor Stem Cell Assay
Myeloproliferative neoplasm
Myelopoiesis
Mice, Inbred BALB C
Mutation
Myeloproliferative Disorders
food and beverages
Exons
Hematology
Janus Kinase 2
Hematopoietic Stem Cells
medicine.disease
Erythropoietin receptor
Enzyme Activation
Phenotype
030104 developmental biology
Oncology
Tyrosine kinase 2
Radiation Chimera
Receptors, Granulocyte Colony-Stimulating Factor
Cancer research
Signal transduction
Cytokine receptor
Cell Division
Signal Transduction
Subjects
Details
- ISSN :
- 14765551 and 08876924
- Volume :
- 31
- Database :
- OpenAIRE
- Journal :
- Leukemia
- Accession number :
- edsair.doi.dedup.....bfa53e5ba8f4b9cddae37aa472bc266e