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

Abstract

Highlights d A selective, orally bioavailable Menin-MLL inhibitor, VTP50469, is developed d Displacement of Menin from chromatin leads to loss of MLL from specific loci d Treatment with VTP50469 leads to suppression of a subset of MLL fusion target genes d Treatment with VTP50469 improves survival in PDX models of MLL-r ALL

NUP98 and KMT2A: usually the bride rather than the bridesmaid

“…Most cases of intestinal T-cell lymphoma were highly aggressive, but in the 1990s there was a series of reports of low-grade intestinal T-cell neoplasms, some of which mimicked lymphomatous polyposis. [4][5][6][7][8] The nature of this rare form of T-cell lymphoma was better defined in sub-sequent reports, 9,10 and incorporated into the Revised 4 th Edition of the World Health Organization (WHO) classification 3 as a provisional entity under the term indolent Tcell lymphoproliferative disorder of the gastrointestinal tract (ITLPD-GIT) (Figure 1). Most patients had a chronic, relapsing clinical course, although in both of the above series late instances of large-cell transformation were described.…”

“…Based on these dependencies, small molecule inhibitors of DOT1L, of BRD4 and of the interaction between KMT2A and MEN1 have been developed. [6][7][8] Other alterations of KMT2A function are observed. In some instances reciprocal X-KMT2A fusions were shown to contribute to leukemogenesis in murine model (e.g.…”

Paediatric Strategy Forum for medicinal product development of epigenetic modifiers for children

“…A phase I trial of a DOT1L inhibitor in patients with MLL-rearranged leukaemia documented minimal toxicity and inhibition of 60e70% of HOX/ MEIS expression, but also illustrated that responses, when observed, may take time to occur and suggested that meaningful antitumour activity would require deep and consistent DOT1L inhibition and use in combination with other drugs [30,31]. Treatment of MLL-r cells with a novel menin-MLL inhibitor, VTP-50469, leads to loss of menin and DOT1L binding on chromatin, producing substantial gene expression/protein changes and dramatic responses in MLL-ALL PDX models [34]. NPM1-mutant leukaemia, a subtype in about 8% of childhood AML16, is also sensitive to the menin-MLL inhibitor, VTP-50469.…”

“…Similar to MLL-r, treatment with VTP-50469 causes loss of menin-chromatin binding and suppression of the leukaemic gene transcription program which leads to decreased MLL-associated gene expression. Dramatic activity in preclinical models of AML (MLL-rearranged and NPM1 mutant) have been observed [32,33,34].…”

Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia

“…While specific molecular dependencies have been identified for some genetic subtypes of AML, such as DOT1L or Menin inhibition for MLL-rearranged leukemias (Krivtsov et al, 2019), and CARM1 inhibition for AML1-rearranged leukemias (Greenblatt et al, 2019), distinct pathogenetic mechanisms of diverse AML subtypes also appear to converge on shared molecular pathways. For example, approximately 25% of adult and childhood AMLs, including both MLLrearranged and non-rearranged cases, require aberrant activation of the transcription factor MEF2C, conferring susceptibility to MARK and SIK inhibitors, which are currently being explored for clinical trials for patients (Brown et al, 2018;Tarumoto et al, 2018;Vakoc and Kentsis, 2018).…”