Jak2-independent hematopoietic cell proliferation and stat5 activation by the kank1-pdgfrb fusion associated with thrombocythemia

Demoulin, Jean Baptiste;Medves, Sandrine;Montano Almendras, Carmen Patricia;Noël, Laura;Constantinescu, Stefan;et.al.
(2011) ISEH 40th Annual Scientific Meeting of the Society-for-Hematology-and-Stem-Cells — Location: Vancouver, CANADA (25.August.2011)

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KANK1-PDGFRB is a fusion gene generated by the t(5;9) translocation between KANK1 and the platelet-derived growth factor (PDGF) receptor beta gene PDGFRB. This hybrid was identified in a myeloproliferative neoplasm featuring severe thrombocythemia, in the absence of JAK2 V617F mutation, which is the most frequent genetic alteration in this disease. The patient responded to imatinib but not to hydroxyurea. Although PDGF receptors are capable of activating JAK2, KANK1-PDGFRB did not induce JAK2 phosphorylation in hematopoietic cells and a JAK inhibitor did not affect KANK1-PDGFRB-induced cell growth. Like JAK2 V617F, KANK1-PDGFRB constitutively activated STAT transcription factors, but this did not require JAK kinases. In addition KANK1-PDGFRB, but not activated JAK2, induced the phosphorylation of phospholipase C-gamma and ERK-1 and -2, like wild-type PDGF receptors and TEL-PDGFRB, another hybrid protein found in myeloid malignancies. To further decipher the mechanism of hematopoietic cell transformation by this fusion gene, we tested various mutant forms of KANK1-PDGFRB in Ba/F3 cells and human CD34+ hematopoietic progenitors. The three coiled coil domains located in the N-terminus of KANK1 were required for KANK1-PDGFRB-induced cell growth and optimal STAT5 activation. However, these protein-protein interaction domains were not essential for KANK1-PDGFRB oligomerization and autophosphorylation. We identified a new oligomerization domain in KANK1-PDGFRB, which was required for cell transformation, in addition to coiled coils. Our results challenge the current hypothesis concerning the absolute role of coiled coil domains in such fusion proteins. KANK1-PDGFRB represent a unique example of genetic alteration associated with thombocythemia in the absence of JAK2 activation.
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Demoulin, J. B., Medves, S., Montano Almendras, C. P., Noël, L., Albu, R. I., Schoemans, H., & Constantinescu, S. (2011). Jak2-independent hematopoietic cell proliferation and stat5 activation by the kank1-pdgfrb fusion associated with thrombocythemia. Experimental Hematology, 39(8), S25. https://hdl.handle.net/2078.5/58149 (Original work published 2011)