TY - JOUR
T1 - A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia
AU - Gu, Ting Lei
AU - Mercher, Thomas
AU - Tyner, Jeffrey W.
AU - Goss, Valerie L.
AU - Walters, Denise K.
AU - Cornejo, Melanie G.
AU - Reeves, Cynthia
AU - Popova, Lana
AU - Lee, Kimberly
AU - Heinrich, Michael C.
AU - Rush, John
AU - Daibata, Masanori
AU - Miyoshi, Isao
AU - Gilliland, D. Gary
AU - Druker, Brian J.
AU - Polakiewicz, Roberto D.
PY - 2007/7/1
Y1 - 2007/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34347384179&partnerID=8YFLogxK
U2 - 10.1182/blood-2006-10-052282
DO - 10.1182/blood-2006-10-052282
M3 - Article
C2 - 17360941
AN - SCOPUS:34347384179
SN - 0006-4971
VL - 110
SP - 323
EP - 333
JO - Blood
JF - Blood
IS - 1
ER -