TY - JOUR
T1 - Proteasome inhibitors evoke latent tumor suppression programs in Pro-B MLL Leukemias through MLL-AF4
AU - Liu, Han
AU - Westergard, Todd D.
AU - Cashen, Amanda
AU - Piwnica-Worms, David R.
AU - Kunkle, Lori
AU - Vij, Ravi
AU - Pham, Can G.
AU - DiPersio, John
AU - Cheng, Emily H.
AU - Hsieh, James J.
N1 - Funding Information:
We apologize to all the investigators whose research could not be appropriately cited owing to space limitations. This work is supported by R01CA119008, R01CA138505, and the Scholar award of the American Cancer Society to J.J.H. and by R01CA125562 to E.H.C. H.L. is supported by the Chinese National Key Basic Research Project (973: 2013CB966801), the National Natural Science Foundation of China (81370651), the Thousand Young Talents program of China, the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, and the American Society of Hematology Scholar Award. We also thank Ms. Wenjing Wu at the MSK Department of Public Affairs for her expert illustration.
PY - 2014/4/14
Y1 - 2014/4/14
N2 - Chromosomal translocations disrupting MLL generate MLL-fusion proteins that induce aggressive leukemias. Unexpectedly, MLL-fusion proteins are rarely observed at high levels, suggesting excessive MLL-fusions may be incompatible with a malignant phenotype. Here, we used clinical proteasome inhibitors, bortezomib and carfilzomib, to reduce the turnover of endogenous MLL-fusions and discovered that accumulated MLL-fusions induce latent, context-dependent tumor suppression programs. Specifically, in MLL pro-B lymphoid, but not myeloid, leukemias, proteasome inhibition triggers apoptosis and cell cycle arrest involving activation cleavage of BID by caspase-8 and upregulation of p27, respectively. Furthermore, proteasome inhibition conferred preliminary benefit to patients with MLL-AF4 leukemia. Hence, feasible strategies to treat cancer-type and oncogene-specific cancers can be improvised through harnessing inherent tumor suppression properties of individual oncogenic fusions.
AB - Chromosomal translocations disrupting MLL generate MLL-fusion proteins that induce aggressive leukemias. Unexpectedly, MLL-fusion proteins are rarely observed at high levels, suggesting excessive MLL-fusions may be incompatible with a malignant phenotype. Here, we used clinical proteasome inhibitors, bortezomib and carfilzomib, to reduce the turnover of endogenous MLL-fusions and discovered that accumulated MLL-fusions induce latent, context-dependent tumor suppression programs. Specifically, in MLL pro-B lymphoid, but not myeloid, leukemias, proteasome inhibition triggers apoptosis and cell cycle arrest involving activation cleavage of BID by caspase-8 and upregulation of p27, respectively. Furthermore, proteasome inhibition conferred preliminary benefit to patients with MLL-AF4 leukemia. Hence, feasible strategies to treat cancer-type and oncogene-specific cancers can be improvised through harnessing inherent tumor suppression properties of individual oncogenic fusions.
UR - http://www.scopus.com/inward/record.url?scp=84898467113&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2014.03.008
DO - 10.1016/j.ccr.2014.03.008
M3 - Article
C2 - 24735925
AN - SCOPUS:84898467113
SN - 1535-6108
VL - 25
SP - 530
EP - 542
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -