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Blood, 1 May 2006, Vol. 107, No. 9, pp. 3495-3502.
Prepublished online as a Blood First Edition Paper on December 29, 2005; DOI 10.1182/blood-2005-07-3037.
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Submitted July 28, 2005
Accepted December 16, 2005
Increased death receptor resistance and FLIPshort expression in polycythemia vera erythroid precursor cells
Ann Zeuner*, Francesca Pedini, Michele Signore, Giusy Ruscio, Carlo Messina, Agostino Tafuri, Gabriella Girelli, Cesare Peschle, and Ruggero De Maria
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome, Italy; Department of Experimental Oncology, Istituto Oncologico del Mediterraneo, Catania, Italy
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome, Italy
Department of Hematology and Cellular Biotechnology, University La Sapienza, Rome, Italy
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome, Italy; Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
* Corresponding author; email: a.zeuner{at}iss.it.
Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by an excessive erythrocyte production. The majority of PV patients harbor an activating JAK2 mutation, but the molecular links between this mutation and erythrocyte overproduction are unknown. The interaction between death receptors and their ligands contributes to the physiological regulation of erythropoiesis through the inhibition of erythroblast proliferation and differentiation. Using an in vitro culture system to generate differentiating erythroid cells, we found that erythroblasts derived from PV patients harboring the JAK2 V617F mutation were
able to proliferate and generate higher numbers of mature erythroid cells in the presence of inhibitory signals delivered by CD95 (Fas/Apo-1) and TRAIL receptor stimulation. JAK2-mutated PV erythroblasts showed lower levels of CD95-induced caspase activation and incomplete caspase-mediated cleavage of the erythroid transcription factor GATA-1, which was entirely degraded in normal erythroblasts upon CD95 stimulation. JAK2 mutation was associated in PV erythroblasts with cytokine-independent activation of the JAK2 effectors Akt/PKB and ERK/MAP and with a deregulated expression of c-FLIPshort, a potent cellular inhibitor of death receptor-induced apoptosis. These results show the presence in PV erythroblasts of proliferative and antiapoptotic signals that may link the JAK2 V617F mutation with inhibition of death receptor signalling, possibly contributing to a deregulation of erythropoiesis.
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