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

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A Menin-MLL Inhibitor Induces Specific Chromatin Changes and Eradicates Disease in Models of MLL-Rearranged Leukemia.
Cancer Cell ( IF 48.8 ) Pub Date : 2019-12-09 , DOI: 10.1016/j.ccell.2019.11.001
Andrei V Krivtsov ₁ , Kathryn Evans ₂ , Jayant Y Gadrey ₁ , Benjamin K Eschle ₁ , Charlie Hatton ₁ , Hannah J Uckelmann ₁ , Kenneth N Ross ₁ , Florian Perner ₁ , Sarah N Olsen ₁ , Tara Pritchard ₂ , Lisa McDermott ₂ , Connor D Jones ₂ , Duohui Jing ₂ , Ali Braytee ₃ , Diego Chacon ₃ , Eric Earley ₄ , Brian M McKeever ₅ , David Claremon ₆ , Andrew J Gifford ₇ , Heather J Lee ₈ , Beverly A Teicher ₉ , John E Pimanda ₁₀ , Dominik Beck ₃ , Jennifer A Perry ₁ , Malcolm A Smith ₉ , Gerard M McGeehan ₁₁ , Richard B Lock ₂ , Scott A Armstrong ₁

Affiliation

Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA.
Children's Cancer Institute, School of Women's and Children's Health, UNSW, Sydney 2052, Australia.
Lowy Cancer Research Centre and the Prince of Wales Clinical School, UNSW, Sydney 2052, Australia; Centre for Health Technologies and the School of Biomedical Engineering, University of Technology Sydney, Ultimo, NSW 2007, Australia.
RTI International, Research Triangle Park, NC 27709, USA.
Brian Michael McKeever, LLC, Lake Ronkonkoma, NY 11779, USA.
CGM Pharma, LLC, Fort Washington, PA 19034, USA.
Children's Cancer Institute, School of Women's and Children's Health, UNSW, Sydney 2052, Australia; Department of Anatomical Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia.
School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW 2308, Australia.
National Cancer Institute, Bethesda, MD 20892, USA.
Lowy Cancer Research Centre and the Prince of Wales Clinical School, UNSW, Sydney 2052, Australia; Department of Haematology, Prince of Wales Hospital, Sydney, NSW 2210, Australia.
Syndax Pharmaceuticals, Waltham, MA 02451, USA.

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.

中文翻译：

Menin-MLL抑制剂在MLL重排的白血病模型中诱导特定的染色质变化并根除疾病。

抑制Menin（MEN1）和MLL（MLL1，KMT2A）相互作用是MLL重排（MLL-r）白血病的潜在治疗策略。基于结构的设计产生了有效的，高选择性的，可口服生物利用的小分子抑制剂VTP50469。带有MLL重排的细胞系对VTP50469有选择性的反应。VTP50469使Menin脱离了蛋白质复合物，并抑制了某些基因上MLL的染色质占据。MLL结合的丧失导致基因表达，分化和凋亡的改变。使用VTP50469治疗时，来自患有MLL-r急性髓细胞性白血病或MLL-r急性淋巴细胞性白血病（ALL）的患者的患者异种移植（PDX）模型显示白血病负担显着降低。治疗后多只移植有MLL-r ALL的小鼠保持无病超过1年。

更新日期：2019-12-11

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