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

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2019 Dec 11

PMID 31821784

Citations 182

Authors

Andrei V Krivtsov

Kathryn Evans

Jayant Y Gadrey

Benjamin K Eschle

Charlie Hatton

Hannah J Uckelmann

Kenneth N Ross

Florian Perner

Sarah N Olsen

Tara Pritchard

Lisa McDermott

Connor D Jones

Duohui Jing

Ali Braytee

Diego Chacon

Eric Earley

Brian M McKeever

David Claremon

Andrew J Gifford

Heather J Lee

Beverly A Teicher

John E Pimanda

Dominik Beck

Jennifer A Perry

Malcolm A Smith

Gerard M McGeehan

Richard B Lock

Scott A Armstrong

Affiliations

Soon will be listed here.

Abstract

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.

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