title: JAK2 V617F-dependent upregulation of PU.1 expression in the peripheral blood of myeloproliferative neoplasm patients.
abstract: Myeloproliferative neoplasms (MPN) are multiple disease entities characterized by clonal expansion of one or more of the myeloid lineages (i.e. granulocytic, erythroid, megakaryocytic and mast cell). JAK2 mutations, such as the common V617F substitution and the less common exon 12 mutations, are frequently detected in such tumor cells and have been incorporated into the diagnostic criteria published by the World Health Organization since 2008. However, the mechanism by which these mutations contribute to MPN development is poorly understood. We examined gene expression profiles of MPN patients focusing on genes in the JAK-STAT signaling pathway using low-density real-time PCR arrays. We identified the following 2 upregulated genes in MPN patients: a known target of the JAK-STAT axis, SOCS3, and a potentially novel target, SPI1, encoding PU.1. Induction of PU.1 expression by JAK2 V617F in JAK2-wildtype K562 cells and its downregulation by JAK2 siRNA transfection in JAK2 V617F-positive HEL cells supported this possibility. We also found that the ABL1 kinase inhibitor imatinib was very effective in suppressing PU.1 expression in BCR-ABL1-positive K562 cells but not in HEL cells. This suggests that PU.1 expression is regulated by both JAK2 and ABL1. The contribution of the two kinases in driving PU.1 expression was dominant for JAK2 and ABL1 in HEL and K562 cells, respectively. Therefore, PU.1 may be a common transcription factor upregulated in MPN. PU.1 is a transcription factor required for myeloid differentiation and is implicated in erythroid leukemia. Therefore, expression of PU.1 downstream of activated JAK2 may explain why JAK2 mutations are frequently observed in MPN patients.
authors.affiliation: Shiga Medical Center for Adults, Moriyama, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Irino
authors.forename: Munehiro
authors.initials: M
authors.lastname: Uemura
authors.forename: Humitsugu
authors.initials: H
authors.lastname: Yamane
authors.forename: Shigeto
authors.initials: S
authors.lastname: Umemura
authors.forename: Takahiko
authors.initials: T
authors.lastname: Utsumi
authors.forename: Naoki
authors.initials: N
authors.lastname: Kakazu
authors.forename: Taku
authors.initials: T
authors.lastname: Shirakawa
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Ito
authors.forename: Takayo
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kinoshita
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics*; D019046:Bone Marrow Neoplasms / Q000097:blood* / Q000201:enzymology / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000097:blood* / Q000201:enzymology / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D053614:Janus Kinase 2; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; C507924:JAK2 protein, human