Eradicating acute myeloid leukemia in a MllPTD/wt:Flt3ITD/wt murine model: A path to novel therapeutic approaches for human disease

Kelsie M. Bernot, John S. Nemer, Ramasamy Santhanam, Shujun Liu, Nicholas A. Zorko, Susan P. Whitman, Kathryn E. Dickerson, Mengzi Zhang, Xiaojuan Yang, Kathleen K. McConnell, Elshafa H. Ahmed, Maura R. Muñoz, Ronald F. Siebenaler, Gabriel G. Marcucci, Bethany L. Mundy-Bosse, Daniel L. Brook, Sabrina Garman, Adrienne M. Dorrance, Xiaoli Zhang, Jianying ZhangRobert J. Lee, William Blum, Michael A. Caligiuri, Guido Marcucci

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3778-3783
Number of pages6
JournalBlood
Volume122
Issue number23
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

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Acute Myeloid Leukemia
Methyltransferases
Therapeutics
Bone
Down-Regulation
Apoptosis
Mutation
Bortezomib
DNA
DNA Methylation
Autopsy
Bone Marrow
Recurrence

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Bernot, K. M., Nemer, J. S., Santhanam, R., Liu, S., Zorko, N. A., Whitman, S. P., ... Marcucci, G. (2013). Eradicating acute myeloid leukemia in a MllPTD/wt:Flt3ITD/wt murine model: A path to novel therapeutic approaches for human disease. Blood, 122(23), 3778-3783. https://doi.org/10.1182/blood-2013-06-507426

Eradicating acute myeloid leukemia in a MllPTD/wt:Flt3ITD/wt murine model : A path to novel therapeutic approaches for human disease. / Bernot, Kelsie M.; Nemer, John S.; Santhanam, Ramasamy; Liu, Shujun; Zorko, Nicholas A.; Whitman, Susan P.; Dickerson, Kathryn E.; Zhang, Mengzi; Yang, Xiaojuan; McConnell, Kathleen K.; Ahmed, Elshafa H.; Muñoz, Maura R.; Siebenaler, Ronald F.; Marcucci, Gabriel G.; Mundy-Bosse, Bethany L.; Brook, Daniel L.; Garman, Sabrina; Dorrance, Adrienne M.; Zhang, Xiaoli; Zhang, Jianying; Lee, Robert J.; Blum, William; Caligiuri, Michael A.; Marcucci, Guido.

In: Blood, Vol. 122, No. 23, 01.01.2013, p. 3778-3783.

Research output: Contribution to journalArticle

Bernot, KM, Nemer, JS, Santhanam, R, Liu, S, Zorko, NA, Whitman, SP, Dickerson, KE, Zhang, M, Yang, X, McConnell, KK, Ahmed, EH, Muñoz, MR, Siebenaler, RF, Marcucci, GG, Mundy-Bosse, BL, Brook, DL, Garman, S, Dorrance, AM, Zhang, X, Zhang, J, Lee, RJ, Blum, W, Caligiuri, MA & Marcucci, G 2013, 'Eradicating acute myeloid leukemia in a MllPTD/wt:Flt3ITD/wt murine model: A path to novel therapeutic approaches for human disease', Blood, vol. 122, no. 23, pp. 3778-3783. https://doi.org/10.1182/blood-2013-06-507426
Bernot, Kelsie M. ; Nemer, John S. ; Santhanam, Ramasamy ; Liu, Shujun ; Zorko, Nicholas A. ; Whitman, Susan P. ; Dickerson, Kathryn E. ; Zhang, Mengzi ; Yang, Xiaojuan ; McConnell, Kathleen K. ; Ahmed, Elshafa H. ; Muñoz, Maura R. ; Siebenaler, Ronald F. ; Marcucci, Gabriel G. ; Mundy-Bosse, Bethany L. ; Brook, Daniel L. ; Garman, Sabrina ; Dorrance, Adrienne M. ; Zhang, Xiaoli ; Zhang, Jianying ; Lee, Robert J. ; Blum, William ; Caligiuri, Michael A. ; Marcucci, Guido. / Eradicating acute myeloid leukemia in a MllPTD/wt:Flt3ITD/wt murine model : A path to novel therapeutic approaches for human disease. In: Blood. 2013 ; Vol. 122, No. 23. pp. 3778-3783.
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abstract = "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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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

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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.

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