Cancer cell, 2019-12, Vol.36 (6), p.660-673.e11
- Krivtsov, Andrei V.
- Evans, Kathryn
- Gadrey, Jayant Y.
- Eschle, Benjamin K.
- Hatton, Charlie
- Uckelmann, Hannah J.
- Ross, Kenneth N.
- Perner, Florian
- Olsen, Sarah N.
- Pritchard, Tara
- McDermott, Lisa
- Jones, Connor D.
- Jing, Duohui
- Braytee, Ali
- Chacon, Diego
- Earley, Eric
- McKeever, Brian M.
- Claremon, David
- Gifford, Andrew J.
- Lee, Heather J.
- Teicher, Beverly A.
- Pimanda, John E.
- Beck, Dominik
- Perry, Jennifer A.
- Smith, Malcolm A.
- McGeehan, Gerard M.
- Lock, Richard B.
- Armstrong, Scott A.
2019
Details
- Autor(en) / Beteiligte
- Krivtsov, Andrei V.
- Evans, Kathryn
- Gadrey, Jayant Y.
- Eschle, Benjamin K.
- Hatton, Charlie
- Uckelmann, Hannah J.
- Ross, Kenneth N.
- Perner, Florian
- Olsen, Sarah N.
- Pritchard, Tara
- McDermott, Lisa
- Jones, Connor D.
- Jing, Duohui
- Braytee, Ali
- Chacon, Diego
- Earley, Eric
- McKeever, Brian M.
- Claremon, David
- Gifford, Andrew J.
- Lee, Heather J.
- Teicher, Beverly A.
- Pimanda, John E.
- Beck, Dominik
- Perry, Jennifer A.
- Smith, Malcolm A.
- McGeehan, Gerard M.
- Lock, Richard B.
- Armstrong, Scott A.
- Titel
- A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia
- Ist Teil von
- Cancer cell, 2019-12, Vol.36 (6), p.660-673.e11
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] •A selective, orally bioavailable Menin-MLL inhibitor, VTP50469, is developed•Displacement of Menin from chromatin leads to loss of MLL from specific loci•Treatment with VTP50469 leads to suppression of a subset of MLL fusion target genes•Treatment with VTP50469 improves survival in PDX models of MLL-r ALL Krivtsov et al. develop a selective and orally bioavailable small-molecule inhibitor targeting the Menin-MLL interaction, which suppresses a subset of MLL fusion target genes and significantly improves survival in PDX models of MLL-rearranged leukemia.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1535-6108eISSN: 1878-3686DOI: 10.1016/j.ccell.2019.11.001Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7227117
- Format
- –
- Schlagworte
- acute myeloid leukemia (AML), Animals, Apoptosis - drug effects, Apoptosis - genetics, Cell Differentiation - drug effects, Cell Differentiation - genetics, Cell Proliferation - drug effects, Cell Proliferation - genetics, Chromatin - drug effects, Chromatin - genetics, chromatin remodeling, DOT1L, Gene Expression Regulation, Leukemic - drug effects, Gene Expression Regulation, Leukemic - genetics, Gene Rearrangement - drug effects, Gene Rearrangement - genetics, Humans, infant B cell acute lymphoblastic leukemia (B-ALL), leukemia, Leukemia, Myeloid, Acute - drug therapy, Leukemia, Myeloid, Acute - genetics, Menin inhibitor, Mice, MLL fusion, Proto-Oncogene Proteins - drug effects, Proto-Oncogene Proteins - genetics, Transcription Factors - drug effects, Transcription Factors - genetics