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The role of the Janus-faced transcription factor PAX5-JAK2 in acute lymphoblastic leukemia
- Source :
- Blood, 125(8), 1282-1291. American Society of Hematology
- Publication Year :
- 2015
- Publisher :
- American Society of Hematology, 2015.
-
Abstract
- PAX5-JAK2 has recently been identified as a novel recurrent fusion gene in B-cell precursor acute lymphoblastic leukemia, but the function of the encoded chimeric protein has not yet been characterized in detail. Herein we show that the PAX5-JAK2 chimera, which consists of the DNA-binding paired domain of PAX5 and the active kinase domain of JAK2, is a nuclear protein that has the ability to bind to wild-type PAX5 target loci. Moreover, our data provide compelling evidence that PAX5-JAK2 functions as a nuclear catalytically active kinase that autophosphorylates and in turn phosphorylates and activates downstream signal transducers and activators of transcription (STATs) in an apparently noncanonical mode. The chimeric protein also enables cytokine-independent growth of Ba/F3 cells and therefore possesses transforming potential. Importantly, the kinase activity of PAX5-JAK2 can be efficiently blocked by JAK2 inhibitors, rendering it a potential target for therapeutic intervention. Together, our data show that PAX5-JAK2 simultaneously deregulates the PAX5 downstream transcriptional program and activates the Janus kinase-STAT signaling cascade and thus, by interfering with these two important pathways, may promote leukemogenesis.
- Subjects :
- Oncogene Proteins, Fusion
Immunology
Mitogen-activated protein kinase kinase
Biochemistry
MAP2K7
immune system diseases
hemic and lymphatic diseases
Tumor Cells, Cultured
Humans
ASK1
c-Raf
Kinase activity
Phosphorylation
Protein Kinase Inhibitors
Janus kinase 2
Lymphoid Neoplasia
biology
Cell Death
Gene Expression Regulation, Leukemic
Cyclin-dependent kinase 2
PAX5 Transcription Factor
food and beverages
Cell Biology
Hematology
Janus Kinase 2
Precursor Cell Lymphoblastic Leukemia-Lymphoma
STAT Transcription Factors
Cell Transformation, Neoplastic
HEK293 Cells
biology.protein
Cancer research
Janus kinase
Transcriptome
hormones, hormone substitutes, and hormone antagonists
HeLa Cells
Subjects
Details
- Language :
- English
- ISSN :
- 00064971
- Database :
- OpenAIRE
- Journal :
- Blood, 125(8), 1282-1291. American Society of Hematology
- Accession number :
- edsair.doi.dedup.....7e78cb4e84305c3460dd72fc92a70257