TY - JOUR
T1 - E6AP ubiquitin ligase regulates PML-induced senescence in Myc-driven lymphomagenesis
AU - Wolyniec, Kamil
AU - Shortt, Jake
AU - De Stanshina, Elisa
AU - Levav-Cohen, Yaara
AU - Alsheich-Bartok, Osnat
AU - Louria-Hayon, Igla
AU - Corneille, Vincent
AU - Kumar, Beena
AU - Woods, Simone J
AU - Opat, Stephen
AU - Johnstone, Ricky W
AU - Scott, Clare L
AU - Segal, David
AU - Pandolfi, Pier Paolo
AU - Fox, Stephen B
AU - Strasser, Andreas
AU - Jiang, Yong-Hui
AU - Lowe, Scott W
AU - Haupt, Sue
AU - Haupt, Yagl
PY - 2012
Y1 - 2012
N2 - Neoplastic transformation requires the elimination of key tumor suppressors, which may result from E3 ligase-mediated proteasomal degradation. We previously demonstrated a key role for the E3 ubiquitin ligase E6AP in the regulation of promyelocytic leukemia protein (PML) stability and formation of PML nuclear bodies. Here, we report the involvement of the E6AP-PML axis in B-cell lymphoma development. A partial loss of E6AP attenuated Myc-induced B-cell lymphomagenesis. This tumor suppressive action was achieved by the induction of cellular senescence. B-cell lymphomas deficient for E6AP expressed elevated levels of PML and PML-nuclear bodies with a concomitant increase in markers of cellular senescence, including p21, H3K9me3, and p16. Consistently, PML deficiency accelerated the rate of Myc-induced B-cell lymphomagenesis. Importantly, E6AP expression was elevated in 60 of human Burkitt lymphomas, and down-regulation of E6AP in B-lymphoma cells restored PML expression with a concurrent induction of cellular senescence in these cells. Our findings demonstrate that E6AP-mediated down-regulation of PML-induced senescence is essential for B-cell lymphoma progression. This provides a molecular explanation for the down-regulation of PML observed in non-Hodgkin lymphomas, thereby suggesting a novel therapeutic approach for restoration of tumor suppression in B-cell lymphoma. ? 2012 by The American Society of Hematology.
AB - Neoplastic transformation requires the elimination of key tumor suppressors, which may result from E3 ligase-mediated proteasomal degradation. We previously demonstrated a key role for the E3 ubiquitin ligase E6AP in the regulation of promyelocytic leukemia protein (PML) stability and formation of PML nuclear bodies. Here, we report the involvement of the E6AP-PML axis in B-cell lymphoma development. A partial loss of E6AP attenuated Myc-induced B-cell lymphomagenesis. This tumor suppressive action was achieved by the induction of cellular senescence. B-cell lymphomas deficient for E6AP expressed elevated levels of PML and PML-nuclear bodies with a concomitant increase in markers of cellular senescence, including p21, H3K9me3, and p16. Consistently, PML deficiency accelerated the rate of Myc-induced B-cell lymphomagenesis. Importantly, E6AP expression was elevated in 60 of human Burkitt lymphomas, and down-regulation of E6AP in B-lymphoma cells restored PML expression with a concurrent induction of cellular senescence in these cells. Our findings demonstrate that E6AP-mediated down-regulation of PML-induced senescence is essential for B-cell lymphoma progression. This provides a molecular explanation for the down-regulation of PML observed in non-Hodgkin lymphomas, thereby suggesting a novel therapeutic approach for restoration of tumor suppression in B-cell lymphoma. ? 2012 by The American Society of Hematology.
UR - http://bloodjournal.hematologylibrary.org/content/120/4/822.full.pdf
U2 - 10.1182/blood-2011-10-387647
DO - 10.1182/blood-2011-10-387647
M3 - Article
SN - 0006-4971
VL - 120
SP - 822
EP - 832
JO - Blood
JF - Blood
IS - 4
ER -