A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia

Krivtsov, AV; Evans, K; Gadrey, JY; Eschle, BK; Hatton, C; Uckelmann, HJ; Ross, KN; Perner, F; Olsen, SN; Pritchard, T; McDermott, L; Jones, CD; Jing, D; Braytee, A; Chacon, D; Earley, E; McKeever, BM; Claremon, D; Gifford, AJ; Lee, HJ; Teicher, BA; Pimanda, JE; Beck, D; Perry, JA; Smith, MA; McGeehan, GM; Lock, RB; Armstrong, SA

A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia

Krivtsov, AV Evans, K Gadrey, JY Eschle, BK Hatton, C Uckelmann, HJ Ross, KN Perner, F Olsen, SN Pritchard, T McDermott, L Jones, CD Jing, D

Braytee, A

Chacon, D

Earley, E McKeever, BM Claremon, D Gifford, AJ Lee, HJ

Teicher, BA Pimanda, JE Beck, D Perry, JA Smith, MA McGeehan, GM Lock, RB Armstrong, SA

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Publication Type:: Journal Article
Citation:: Cancer Cell, 2019, 36 (6), pp. 660 - 673.e11
Issue Date:: 2019-12-09

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Field	Value	Language
dc.contributor.author	Krivtsov, AV	en_US
dc.contributor.author	Evans, K	en_US
dc.contributor.author	Gadrey, JY	en_US
dc.contributor.author	Eschle, BK	en_US
dc.contributor.author	Hatton, C	en_US
dc.contributor.author	Uckelmann, HJ	en_US
dc.contributor.author	Ross, KN	en_US
dc.contributor.author	Perner, F	en_US
dc.contributor.author	Olsen, SN	en_US
dc.contributor.author	Pritchard, T	en_US
dc.contributor.author	McDermott, L	en_US
dc.contributor.author	Jones, CD	en_US
dc.contributor.author	Jing, D https://orcid.org/0000-0002-1491-8002	en_US
dc.contributor.author	Braytee, A https://orcid.org/0000-0003-2561-6496	en_US
dc.contributor.author	Chacon, D https://orcid.org/0000-0003-3729-1385	en_US
dc.contributor.author	Earley, E	en_US
dc.contributor.author	McKeever, BM	en_US
dc.contributor.author	Claremon, D	en_US
dc.contributor.author	Gifford, AJ	en_US
dc.contributor.author	Lee, HJ https://orcid.org/0000-0002-6482-0337	en_US
dc.contributor.author	Teicher, BA	en_US
dc.contributor.author	Pimanda, JE	en_US
dc.contributor.author	Beck, D	en_US
dc.contributor.author	Perry, JA	en_US
dc.contributor.author	Smith, MA	en_US
dc.contributor.author	McGeehan, GM	en_US
dc.contributor.author	Lock, RB	en_US
dc.contributor.author	Armstrong, SA	en_US
dc.date.available	2019-11-04	en_US
dc.date.issued	2019-12-09	en_US
dc.identifier.citation	Cancer Cell, 2019, 36 (6), pp. 660 - 673.e11	en_US
dc.identifier.issn	1535-6108	en_US
dc.identifier.uri	http://hdl.handle.net/10453/137536
dc.description.abstract	© 2019 Elsevier Inc. Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the potent, highly selective, and orally bioavailable small-molecule inhibitor VTP50469. Cell lines carrying MLL rearrangements were selectively responsive to VTP50469. VTP50469 displaced Menin from protein complexes and inhibited chromatin occupancy of MLL at select genes. Loss of MLL binding led to changes in gene expression, differentiation, and apoptosis. Patient-derived xenograft (PDX) models derived from patients with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblastic leukemia (ALL) showed dramatic reductions of leukemia burden when treated with VTP50469. Multiple mice engrafted with MLL-r ALL remained disease free for more than 1 year after treatment. These data support rapid translation of this approach to clinical trials.	en_US
dc.relation.ispartof	Cancer Cell	en_US
dc.relation.isbasedon	10.1016/j.ccell.2019.11.001	en_US
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject.classification	Oncology & Carcinogenesis	en_US
dc.title	A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia	en_US
dc.type	Journal Article
utslib.citation.volume	6	en_US
utslib.citation.volume	36	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	1112 Oncology and Carcinogenesis	en_US
utslib.for	1109 Neurosciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Computer Science
pubs.organisational-group	/University of Technology Sydney/Strength - AAI - Advanced Analytics Institute Research Centre
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access	*
pubs.issue	6	en_US
pubs.publication-status	Published	en_US
pubs.volume	36	en_US

Abstract:

© 2019 Elsevier Inc. Inhibition of the Menin (MEN1) and MLL (MLL1, KMT2A) interaction is a potential therapeutic strategy for MLL-rearranged (MLL-r) leukemia. Structure-based design yielded the potent, highly selective, and orally bioavailable small-molecule inhibitor VTP50469. Cell lines carrying MLL rearrangements were selectively responsive to VTP50469. VTP50469 displaced Menin from protein complexes and inhibited chromatin occupancy of MLL at select genes. Loss of MLL binding led to changes in gene expression, differentiation, and apoptosis. Patient-derived xenograft (PDX) models derived from patients with either MLL-r acute myeloid leukemia or MLL-r acute lymphoblastic leukemia (ALL) showed dramatic reductions of leukemia burden when treated with VTP50469. Multiple mice engrafted with MLL-r ALL remained disease free for more than 1 year after treatment. These data support rapid translation of this approach to clinical trials.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/137536