A Novel Fusion of RBM6 to CSF1R in Acute Megakaryoblastic Leukemia

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2007 Mar 16

PMID 17360941

Citations 21

Authors

Ting-Lei Gu

Thomas Mercher

Jeffrey W Tyner

Valerie L Goss

Denise K Walters

Melanie G Cornejo

Cynthia Reeves

Lana Popova

Kimberly Lee

Michael C Heinrich

John Rush

Masanori Daibata

Isao Miyoshi

D Gary Gilliland

Brian J Druker

Roberto D Polakiewicz

Affiliations

Soon will be listed here.

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.

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