Complementary activities of DOT1L and Menin inhibitors in MLL-rearranged leukemia

Abstract

Chromosomal rearrangements of the mixed lineage leukemia (MLL/KMT2A) gene leading to oncogenic MLL-fusion proteins occur in ~10% of acute leukemias and are associated with poor clinical outcomes, emphasizing the need for new treatment modalities. Inhibition of the DOT1-like histone H3K79 methyltransferase (DOT1L) is a specific therapeutic approach for such leukemias that is currently being tested in clinical trials. However, in most MLL-rearranged leukemia models responses to DOT1L inhibitors are limited. Here, we performed deep-coverage short hairpin RNA sensitizer screens in DOT1L inhibitor-treated MLL-rearranged leukemia cell lines and discovered that targeting additional nodes of MLL complexes concomitantly with DOT1L inhibition bears great potential for superior therapeutic results. Most notably, combination of a DOT1L inhibitor with an inhibitor of the MLL-Menin interaction markedly enhanced induction of differentiation and cell killing in various MLL disease models including primary leukemia cells, while sparing normal hematopoiesis and leukemias without MLL rearrangements. Gene expression analysis on human and murine leukemic cells revealed that target genes of MLL-fusion proteins and MYC were suppressed more profoundly upon combination treatment. Our findings provide a strong rationale for a novel targeted combination therapy that is expected to improve therapeutic outcomes in patients with MLL-rearranged leukemia.

MLLT10 rearranged acute leukemia: Incidence, prognosis, and possible therapeutic strategies

“…80 Instead, a combinatorial approach of therapies targeted towards different pathways, and/or in addition to conventional cytotoxic chemotherapeutics is likely to prove an optimal approach. Inhibitors targeting HDAC, 102 BET, 103,104 and menin 81…”

Target identification reveals lanosterol synthase as a vulnerability in glioma

“…In this report, we characterize the mechanism of action of MI-2, a drug previously identified in a small molecule screen, as having a therapeutic effect in preclinical DIPG and glioma models. Elegant studies have demonstrated MI-2 is a menin inhibitor (7,8), and in MLL-fusion leukemia cells, interruption of the menin-MLL interaction has a well-established mechanistic link to suppression of leukemia growth (7,8,12,13,29). In the context of glioma, however, although menin is expressed, our data show it is not a major target responsible for the antitumor effects observed after MI-2 treatment.…”

New and Emerging Targeted Therapies for Pediatric Acute Myeloid Leukemia (AML)

“…Targeting more than one component of the KMT2A complex has great potential for targeted treatment. Although a DOT1L inhibitor by itself has not shown promising results in Phase I trials, Dafflon et al showed that the combination of a DOT1L inhibitor and a menin inhibitor demonstrated robust synergy in its anti-leukemic growth inhibition effect in a mouse model injected with KMT2A-AF9 leukemic cells, compared to either drug alone [44,52]. Further studies will be needed to investigate whether the combination of Pinometostat with another anti-leukemic agent can improve its efficacy.…”