Increased death receptor resistance and FLIPshort expression in polycythemia vera erythroid precursor cells.
Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by excessive erythrocyte production. Most patients with PV 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. With the use of an in vitro culture system to generate differentiating erythroid cells, we found that erythroblasts derived from patients with PV 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 on 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-FLIP(short), 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 the inhibition of death receptor signaling, possibly contributing to a deregulation of erythropoiesis.
Zeuner
Ann
A
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. a.zeuner@iss.it
Pedini
Francesca
F
Signore
Michele
M
Ruscio
Giusy
G
Messina
Carlo
C
Tafuri
Agostino
A
Girelli
Gabriella
G
Peschle
Cesare
C
De Maria
Ruggero
R
D000328:Adult; D000368:Aged; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000473:pathology; D004920:Erythropoiesis; D005260:Female; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D053614:Janus Kinase 2; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011087:Polycythemia Vera / Q000097:blood* / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood*; D019014:fas Receptor / Q000378:metabolism
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2