Haematologica, Vol 93, Issue 1, 49-56 doi:10.3324/haematol.11836
Copyright © 2008 by Ferrata Storti Foundation

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Myeloproliferative Disorders

Activity of imatinib in systemic mastocytosis with chronic basophilic leukemia and a PRKG2-PDGFRB fusion

Idoya Lahortiga^1,2, Cem Akin³, Jan Cools^1,2, Todd M. Wilson⁴, Nicole Mentens^1,2, Diane C. Arthur⁵, Irina Maric⁶, Pierre Noel¹, Can Kocabas⁴, Peter Marynen², Lawrence S. Lessin⁷, Iwona Wlodarska², Jamie Robyn⁴, Dean D. Metcalfe^4,

¹ Human Genome Laboratory, Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium
² Center for Human Genetics, University of Leuven, Leuven, Belgium
³ Allergy and Clinical Immunology, University of Michigan, Ann Arbor, MI, USA
⁴ Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
⁵ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
⁶ Department of Laboratory Medicine, National Institutes of Health, USA and
⁷ Washington Cancer Institute, Washington Hospital Center, Washington, DC, USA

Correspondence: Dean D. Metcalfe, Laboratory of Allergic Diseases, NIAID, NIH, DHHS, Building 10, Room 11C205, 10 Center Drive - MSC1881, Bethesda, MD 20892-1881 USA. E-mail: dmetcalfe{at}niaid.nih.gov

Background: Translocations involving region 5q31-32 (PDGFRB) have been reported in a variety of myeloproliferative diseases and are often associated with significant peripheral eosinophilia. We report an unusual case of a patient presenting with peripheral basophilia and systemic mastocytosis in whom cytogenetic analysis revealed a t(4;5)(q21.1;q31.3).

Design and Methods: We used molecular analyses to determine the role of PDGFRB in this case. The patient was treated with imatinib.

Results: Fluorescence in situ hybridization (FISH) documented a breakpoint in PDGFRB. In agreement with this, the patient responded very well to imatinib with resolution of clinical symptoms, basophilia, and mast cell disease. Molecular analyses revealed that PDGFRB, encoding an imatinib-sensitive tyrosine kinase, was fused to PRKG2. The fusion gene incorporates the first two exons of PRKG2 fused to the truncated exon 12 of PDGFRB, resulting in the disruption of its juxtamembrane domain. Functional studies confirmed that the activity and transforming properties of PRKG2-PDGFRβ were dependent on the disruption of the auto-inhibitory juxtamembrane domain.

Conclusions: Our results identify a second case of the PRKG2-PDGFRB fusion and confirm the unusual PDGFRB breakpoint associated with this fusion. This work also illustrates the use of imatinib for the treatment of specific cases of systemic mastocytosis.

Key words: systemic mastocytosis, chronic basophilic leukemia, PRKG2-PDGFRB, imatinib.

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