Synergistic Strategies for KMT2A-Rearranged Leukemias: Beyond Menin Inhibitor

Abstract

KMT2A-rearranged leukemias are a highly aggressive subset of acute leukemia, characterized by poor prognosis and frequent relapses despite intensive treatment. Menin inhibitors, which target the critical KMT2A-menin interaction driving leukemogenesis, have shown promise in early clinical trials. However, resistance to these inhibitors, often driven by menin mutations or alternative oncogenic pathways, remains a significant challenge. This review explores combination therapies aimed at overcoming resistance and improving patient outcomes. Potential strategies include inhibiting DOT1L, a histone methyltransferase essential for KMT2A-driven transcription, and BRD4, a regulator of transcriptional super-enhancers. Additionally, targeting MYC, a key oncogene frequently upregulated in KMT2A-rearranged leukemia, offers another approach. Direct inhibition of KMT2A-fusion proteins and c-MYB, a transcription factor critical for leukemic stem cell maintenance, is also explored. By integrating these diverse strategies, we propose a comprehensive therapeutic paradigm that targets multiple points of the leukemic transcriptional and epigenetic network. These combination approaches aim to disrupt key oncogenic pathways, reduce resistance, and enhance treatment efficacy, ultimately providing more durable remissions and improved survival for patients with KMT2A-rearranged leukemias.

Keywords: KMT2A-rearranged leukemia; acute myeloid leukemia; combination therapies; menin inhibitors; targeted therapies; therapeutic resistance.

Figure 1

Role of KMT2A rearrangements in leukemogenesis and protein complexes of KMT2A fusion partners. The KMT2A gene, which encodes H3K4 methyltransferase, frequently undergoes chromosomal translocations, generating more than 50 distinct KMT2A fusion proteins (KMT2A-FP). These fusion proteins retain key interactions with menin, which acts as a critical scaffold by anchoring LEDGF and the PAFc complex to KMT2A fusions. This interaction facilitates the recruitment of transcriptional machinery to chromatin, driving the expression of oncogenes. Despite these retained interactions, KMT2A fusion proteins lose key regions responsible for H3K4 methylation, such as the PHD finger and SET domains, impairing normal gene regulation. Some major KMT2A fusion proteins directly recruit DOT1L, a histone methyltransferase that catalyzes H3K79 methylation. Others indirectly recruit DOT1L through p-TEFb. This misdirected DOT1L activity leads to aberrant H3K79 methylation and activation of leukemogenic genes. Additionally, most KMT2A fusion proteins recruit the super elongation complex (SEC), which, along with PAFc, interacts with BRD4, a BET family member that binds acetylated histones via its bromodomains, contributing to transcriptional dysregulation. The resulting upregulation of proto-oncogenes, including HOXA, MEIS1, c-MYB, and MYC, drives the leukemogenic process, making menin a key therapeutic target in KMT2Ar leukemias.

Figure 2

Key components and therapeutic targets in KMT2Ar leukemia. This schematic illustrates the KMT2Ar fusion complex at target gene loci. Highlighted are key components of this complex, including menin, DOT1L, and BRD4, which are essential for KMT2A fusion-mediated transformation and are targeted by small molecule inhibitors, as indicated. Also shown are the downstream targets of the KMT2A fusion protein—c-MYB, MYC—that play crucial roles in leukemogenesis. Small molecule inhibitors targeting these pathways are also indicated.