Activation of FIP1L1-PDGFRα requires disruption of the juxtamembrane domain of PDGFRα and is FIP1L1-independent

doi:10.1073/pnas.0601192103

Activation of FIP1L1-PDGFRα requires disruption of the juxtamembrane domain of PDGFRα and is FIP1L1-independent

*Division of Hematology, Department of Medicine, and
^¶Department of Pathology, Brigham and Women's Hospital,
^†Department of Genetics, and
**Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115;
^‡Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322;
^§Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Leuven, 3000 Leuven, Belgium; and
^‖Department of Pathology, Emory University, Atlanta, GA 30322

Edited by Owen N. Witte, University of California, Los Angeles, CA, and approved April 10, 2006 (received for review February 12, 2006)

Abstract

Genetic abnormalities that result in expression of chimeric tyrosine kinase proteins such as BCR-ABL1 and ETV6-PDGFRβ are common causes of hematopoietic malignancies. The paradigm for constitutive activation of these fusion tyrosine kinases is enforced homodimerization by self-association domains present in the fusion partner proteins. The unique interstitial deletion on chromosome 4q12 that leads to expression of the FIP1L1-PDGFRα fusion tyrosine kinase was recently identified as a cause of chronic eosinophilic leukemia. In this report, we demonstrate that FIP1L1 is completely dispensable for PDGFRα activation in vitro and in vivo. Instead, truncation of PDGFRα between two conserved tryptophan residues in the juxtamembrane (JM) domain is required for kinase activation and transforming potential of FIP1L1-PDGFRα. The presence of a complete JM domain in FIP1L1-PDGFRα is inhibitory, but this autoinhibition can be overcome by enforced homodimerization. Similar effects of the JM domain in the context of PDGFRβ were observed. These results suggest that disruption of the autoinhibitory JM domain is an alternative, dimerization-independent mechanism by which chimeric tyrosine kinases are constitutively activated and induce leukemogenesis.

Footnotes

^††To whom correspondence may be addressed. E-mail: ggilliland{at}rics.bwh.harvard.edu or jan.cools{at}med.kuleuven.be
Author contributions: E.H.S., J. Chen, P.M., D.G.G., and J. Cools designed research; E.H.S., J. Chen, C.F., B.H.L., N.M., I.R.W., and J. Cools performed research; E.H.S., J. Chen, P.M., D.G.G., B.H.L., and I.R.W. contributed new reagents/analytic tools; J. Cools analyzed data; and E.H.S., J. Chen, P.M., D.G.G., and J. Cools wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

CEL,

chronic eosinophilic leukemia;

JM,

juxtamembrane;

RTK,

receptor tyrosine kinase