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Blood, 1 July 2007, Vol. 110, No. 1, pp. 323-333.
Prepublished online as a Blood First Edition Paper on April 13, 2007March 14, 2007; DOI 10.1182/blood-2006-10-052282.
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Submitted October 17, 2006
Accepted March 11, 2007
A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia
Ting-lei Gu, Thomas Mercher, Jeffrey W. Tyner, Valerie L. Goss, Denise K. Walters, Melanie G. Cornejo, Cynthia Reeves, Lana Popova, Kimberly Lee, John Rush, Masanori Daibata, Isao Miyoshi, D. Gary Gilliland, Brian J. Druker, and Roberto D Polakiewicz*
Cell Signaling Technology, Inc., Danvers, MA
Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA
Department of Hematology and Oncology, Howard Hughes Medical Institute, Oregon Health & Science University Cancer Institute, Portland, OR
Department of Medicine, Kochi Medical School, Kochi University, Kochi, Japan
* Corresponding author; email: rpolakiewicz{at}cellsignal.com.
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 employed 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 employing 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.
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