TY - JOUR
T1 - Eradicating acute myeloid leukemia in a MllPTD/wt:Flt3ITD/wt murine model
T2 - A path to novel therapeutic approaches for human disease
AU - Bernot, Kelsie M.
AU - Nemer, John S.
AU - Santhanam, Ramasamy
AU - Liu, Shujun
AU - Zorko, Nicholas A.
AU - Whitman, Susan P.
AU - Dickerson, Kathryn E.
AU - Zhang, Mengzi
AU - Yang, Xiaojuan
AU - McConnell, Kathleen K.
AU - Ahmed, Elshafa H.
AU - Muñoz, Maura R.
AU - Siebenaler, Ronald F.
AU - Marcucci, Gabriel G.
AU - Mundy-Bosse, Bethany L.
AU - Brook, Daniel L.
AU - Garman, Sabrina
AU - Dorrance, Adrienne M.
AU - Zhang, Xiaoli
AU - Zhang, Jianying
AU - Lee, Robert J.
AU - Blum, William
AU - Caligiuri, Michael A.
AU - Marcucci, Guido
N1 - Publisher Copyright:
© 2013 by The American Society of Hematology.
PY - 2013/11/28
Y1 - 2013/11/28
N2 - The coexpression of the MLL partial tandem duplication (PTD) and the FLT3 internal tandem duplication (ITD) mutations associate with a poor outcome in cytogenetically normal acute myeloid leukemia (AML). In mice, a double knock-in (dKI) of MllPTD/wt and Flt3ITD/wt mutations induces spontaneous AML with an increase in DNA methyltransferases (Dnmt1, 3a, and 3b) and global DNA methylation index, thereby recapitulating its human AML counterpart. We determined that a regulator of Dnmts, miR-29b, is downregulated in bone marrow of dKI AML mice. Bortezomib exerted a dose-dependent increase in miR-29b expression in AML blasts ex vivo, followed by decreased Dnmts, reduced proliferation, and increased apoptosis. In vivo, bortezomib was not active against dKI AML, yet liposomal-encapsulated bortezomib, as a single agent, reversed downregulation of miR-29b in vivo and induced a long-term (90-day) disease-free remission in 80% of dKI AML mice that exhibited high leukemic burden at the start of therapy, yet showed no signs of relapse at autopsy. Taken together, these data support that liposomal bortezomib, as a single agent, eradicates MllPTD/wt:Flt3ITD/wt AML in mouse and may represent a powerful and potentially curative approach to high-risk human disease.
AB - The coexpression of the MLL partial tandem duplication (PTD) and the FLT3 internal tandem duplication (ITD) mutations associate with a poor outcome in cytogenetically normal acute myeloid leukemia (AML). In mice, a double knock-in (dKI) of MllPTD/wt and Flt3ITD/wt mutations induces spontaneous AML with an increase in DNA methyltransferases (Dnmt1, 3a, and 3b) and global DNA methylation index, thereby recapitulating its human AML counterpart. We determined that a regulator of Dnmts, miR-29b, is downregulated in bone marrow of dKI AML mice. Bortezomib exerted a dose-dependent increase in miR-29b expression in AML blasts ex vivo, followed by decreased Dnmts, reduced proliferation, and increased apoptosis. In vivo, bortezomib was not active against dKI AML, yet liposomal-encapsulated bortezomib, as a single agent, reversed downregulation of miR-29b in vivo and induced a long-term (90-day) disease-free remission in 80% of dKI AML mice that exhibited high leukemic burden at the start of therapy, yet showed no signs of relapse at autopsy. Taken together, these data support that liposomal bortezomib, as a single agent, eradicates MllPTD/wt:Flt3ITD/wt AML in mouse and may represent a powerful and potentially curative approach to high-risk human disease.
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U2 - 10.1182/blood-2013-06-507426
DO - 10.1182/blood-2013-06-507426
M3 - Article
C2 - 24085765
AN - SCOPUS:84892879433
SN - 0006-4971
VL - 122
SP - 3778
EP - 3783
JO - Blood
JF - Blood
IS - 23
ER -