title: A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia.
abstract: Activated tyrosine kinases have been frequently implicated in the pathogenesis of cancer, including acute myeloid leukemia (AML), and are validated targets for therapeutic intervention with small-molecule kinase inhibitors. To identify novel activated tyrosine kinases in AML, we used a discovery platform consisting of immunoaffinity profiling coupled to mass spectrometry that identifies large numbers of tyrosine-phosphorylated proteins, including active kinases. This method revealed the presence of an activated colony-stimulating factor 1 receptor (CSF1R) kinase in the acute megakaryoblastic leukemia (AMKL) cell line MKPL-1. Further studies using siRNA and a small-molecule inhibitor showed that CSF1R is essential for the growth and survival of MKPL-1 cells. DNA sequence analysis of cDNA generated by 5'RACE from CSF1R coding sequences identified a novel fusion of the RNA binding motif 6 (RBM6) gene to CSF1R gene generated presumably by a t(3;5)(p21;q33) translocation. Expression of the RBM6-CSF1R fusion protein conferred interleukin-3 (IL-3)-independent growth in BaF3 cells, and induces a myeloid proliferative disease (MPD) with features of megakaryoblastic leukemia in a murine transplant model. These findings identify a novel potential therapeutic target in leukemogenesis, and demonstrate the utility of phosphoproteomic strategies for discovery of tyrosine kinase alleles.
authors.affiliation: Cell Signaling Technology, Danvers, MA 01923, USA.
authors.forename: Ting-lei
authors.initials: TL
authors.lastname: Gu
authors.forename: Thomas
authors.initials: T
authors.lastname: Mercher
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Goss
authors.forename: Denise K
authors.initials: DK
authors.lastname: Walters
authors.forename: Melanie G
authors.initials: MG
authors.lastname: Cornejo
authors.forename: Cynthia
authors.initials: C
authors.lastname: Reeves
authors.forename: Lana
authors.initials: L
authors.lastname: Popova
authors.forename: Kimberly
authors.initials: K
authors.lastname: Lee
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: John
authors.initials: J
authors.lastname: Rush
authors.forename: Masanori
authors.initials: M
authors.lastname: Daibata
authors.forename: Isao
authors.initials: I
authors.lastname: Miyoshi
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Roberto D
authors.initials: RD
authors.lastname: Polakiewicz
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002893:Chromosomes, Human, Pair 3; D002895:Chromosomes, Human, Pair 5; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000209:etiology / Q000235:genetics*; D051379:Mice; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000302:isolation & purification; D016601:RNA-Binding Proteins / Q000235:genetics*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000302:isolation & purification; D017422:Sequence Analysis, DNA; D014178:Translocation, Genetic; D014183:Transplantation, Heterologous
chemical_list: D015514:Oncogene Proteins, Fusion; C120511:RBM6 protein, human; D016601:RNA-Binding Proteins; D011505:Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor