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

Idoya Lahortiga, Cem Akin, Jan Cools, Todd M. Wilson, Nicole Mentens, Diane C. Arthur, Irina Maric, Pierre Noel, Can Kocabas, Peter Marynen, Lawrence S. Lessin, Iwona Wlodarska, Jamie Robyn, Dean D. Metcalfe

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)49-56
Number of pages8
JournalHaematologica
Volume93
Issue number1
DOIs
StatePublished - Jan 2008
Externally publishedYes

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Systemic Mastocytosis
Platelet-Derived Growth Factor beta Receptor
Leukemia
Exons
Mastocytosis
Cytogenetic Analysis
Gene Fusion
Eosinophilia
Imatinib Mesylate
Fluorescence In Situ Hybridization
Protein-Tyrosine Kinases

Keywords

  • Chronic basophilic leukemia
  • Imatinib
  • PRKG2-PDGFRB
  • Systemic mastocytosis

ASJC Scopus subject areas

  • Hematology

Cite this

Lahortiga, I., Akin, C., Cools, J., Wilson, T. M., Mentens, N., Arthur, D. C., ... Metcalfe, D. D. (2008). Activity of imatinib in systemic mastocytosis with chronic basophilic leukemia and a PRKG2-PDGFRB fusion. Haematologica, 93(1), 49-56. https://doi.org/10.3324/haematol.11836

Activity of imatinib in systemic mastocytosis with chronic basophilic leukemia and a PRKG2-PDGFRB fusion. / Lahortiga, Idoya; Akin, Cem; Cools, Jan; Wilson, Todd M.; Mentens, Nicole; Arthur, Diane C.; Maric, Irina; Noel, Pierre; Kocabas, Can; Marynen, Peter; Lessin, Lawrence S.; Wlodarska, Iwona; Robyn, Jamie; Metcalfe, Dean D.

In: Haematologica, Vol. 93, No. 1, 01.2008, p. 49-56.

Research output: Contribution to journalArticle

Lahortiga, I, Akin, C, Cools, J, Wilson, TM, Mentens, N, Arthur, DC, Maric, I, Noel, P, Kocabas, C, Marynen, P, Lessin, LS, Wlodarska, I, Robyn, J & Metcalfe, DD 2008, 'Activity of imatinib in systemic mastocytosis with chronic basophilic leukemia and a PRKG2-PDGFRB fusion', Haematologica, vol. 93, no. 1, pp. 49-56. https://doi.org/10.3324/haematol.11836
Lahortiga, Idoya ; Akin, Cem ; Cools, Jan ; Wilson, Todd M. ; Mentens, Nicole ; Arthur, Diane C. ; Maric, Irina ; Noel, Pierre ; Kocabas, Can ; Marynen, Peter ; Lessin, Lawrence S. ; Wlodarska, Iwona ; Robyn, Jamie ; Metcalfe, Dean D. / Activity of imatinib in systemic mastocytosis with chronic basophilic leukemia and a PRKG2-PDGFRB fusion. In: Haematologica. 2008 ; Vol. 93, No. 1. pp. 49-56.
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AU - Wilson, Todd M.

AU - Mentens, Nicole

AU - Arthur, Diane C.

AU - Maric, Irina

AU - Noel, Pierre

AU - Kocabas, Can

AU - Marynen, Peter

AU - Lessin, Lawrence S.

AU - Wlodarska, Iwona

AU - Robyn, Jamie

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AB - 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.

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