| Title: |
A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia |
| Authors: |
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; Chacon Fajardo, Diego |
| Source: |
urn:ISSN:1535-6108 ; urn:ISSN:1878-3686 ; Cancer Cell, 36, 6, 660-673.e11 |
| Publisher Information: |
Elsevier |
| Publication Year: |
2019 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
3101 Biochemistry and Cell Biology; 32 Biomedical and Clinical Sciences; 31 Biological Sciences; Hematology; Genetics; Cancer; Childhood Leukemia; Biotechnology; Pediatric Research Initiative; Rare Diseases; Orphan Drug; Pediatric Cancer; 5.1 Pharmaceuticals; Animals; Apoptosis; Cell Differentiation; Cell Proliferation; Chromatin; Gene Expression Regulation; Leukemic; Gene Rearrangement; Humans; Leukemia; Myeloid; Acute; Mice; Proto-Oncogene Proteins; Transcription Factors; DOT1L; MLL fusion |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
http://purl.org/au-research/grants/nhmrc/APP1059804; http://purl.org/au-research/grants/nhmrc/APP1157871; https://hdl.handle.net/1959.4/unsworks_63330; https://doi.org/10.1016/j.ccell.2019.11.001 |
| DOI: |
10.1016/j.ccell.2019.11.001 |
| Availability: |
https://hdl.handle.net/1959.4/unsworks_63330; https://unsworks.unsw.edu.au/bitstreams/413cc489-033c-482b-aeb6-413956541e76/download; https://doi.org/10.1016/j.ccell.2019.11.001 |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC-BY-NC-ND ; https://creativecommons.org/licenses/by-nc-nd/4.0/ ; free_to_read |
| Accession Number: |
edsbas.7216D8C8 |
| Database: |
BASE |