| Autor: |
Tayari, Mina M., Totiger, Tulasigeri M, Shiekhattar, Ramin, Taylor, Justin, Watts, Justin M. |
| Zdroj: |
Blood; November 2023, Vol. 142 Issue: 1, Number 1 Supplement 1 p5691-5691, 1p |
| Abstrakt: |
Introduction: Menin is a scaffold protein that binds to gene promoters, enhancers and transcription factors, thereby influencing transcription. Leukemias with rearrangement of KMT2Aknown as mixed-lineage leukemia (MLL), as well as other abnormalities such as NPM1c, respond to Menin inhibition with promising early clinical results. MLL leukemias affect children and adults and are associated with high rates of resistance to conventional chemotherapy. In addition to these alterations, other leukemia subsets with similar transcriptional dependency could be targeted through Menin inhibition. LSD1 is an essential regulator of murine MLL-AF9 leukemia stem cells (LSCs) and maintains the LSC potential of MLL-AML cells through blocking of differentiation and apoptosis ( Harris et al, 2012). LSD1 acts at genomic loci that are bound by MLL-AF9 to maintain expression of the associated leukemogenic program, thus preventing differentiation and apoptosis. We investigated the pre-clinical efficacy of combined Menin and LSD1 inhibition in AML. PC4 and SF2 interacting protein 1 (PSIP1)/p75, also known as LEDGF, interacts with the N-terminus of MLL and Menin. This complex contributes to the association of MLL and MLL-fusion multiprotein complexes with the chromatin. Several studies have shown that both PSIP1 and Menin are required for efficient MLL-fusion-mediated leukemogenesis and for the expression of MLL-regulated genes. A proposed model of LSD1 interaction with KMT2A-Menin-PSIP1 suprcomplex is depicted in Fig. 1A. |
| Databáze: |
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