Increased death receptor resistance and FLIPshort expression in polycythemia vera erythroid precursor cells.

Abstract:

: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.

journal_name

Blood

journal_title

Blood

authors

Zeuner A,Pedini F,Signore M,Ruscio G,Messina C,Tafuri A,Girelli G,Peschle C,De Maria R

doi

10.1182/blood-2005-07-3037

subject

Has Abstract

pub_date

2006-05-01 00:00:00

pages

3495-502

issue

9

eissn

0006-4971

issn

1528-0020

pii

2005-07-3037

journal_volume

107

pub_type

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