Biology subjects

Tayari, M. M.

Publications and source records attributed to Tayari, M. M..

3 recordsLinked to original sources

bioRxiv2025

Co-targeting menin and LSD1 dismantles oncogenic programs and restores differentiation in MLL-rearranged AML

Acute myeloid leukemia (AML) harboring MLL (MLL1, KMT2A) rearrangement (MLL-r) remains a lethal subtype with limited durable responses to single-agent menin inhibition. To define rational combination strategies, we performed a high-throughput screen of >900 epigenetic modulators in combination with menin inhibition in MLL-r AML models. This uncovered consistent synergy between menin and lysine-specific demethylase 1 (LSD1) inhibition, including with the clinical agent iadademstat. Mechanistically, LSD1 was found to interact with LEDGF/p75 (PSIP1), a chromatin-anchoring cofactor of the menin-MLL complex at H3K36me3 marked euchromatin. Chromatin profiling revealed extensive co-occupancy of LSD1 and menin-MLL components at leukemogenic loci in MLL-r AML cells. Dual inhibition of menin and LSD1 dismantled this chromatin complex, evicted H3K36me3 from LEDGF-bound sites, and reprogrammed transcription toward myeloid differentiation. Combined menin and LSD1 blockade repressed canonical MLL targets, including HOXA9, MYC, FLT3, PBX3, and CDK6, while restoring H3K36me3 and H3K4me3 and activating differentiation-associated genes. In vivo, the combination produced potent antileukemic effects in both MOLM-13 and MLL-r patient-derived xenografts, markedly reducing leukemic burden and extending survival without overt toxicity. These findings identify LSD1 as a critical cofactor of the menin-MLL-LEDGF axis and establish concurrent menin and LSD1 inhibition as a mechanistically informed combinatorial therapeutic approach in MLL-r AML.

cancer biology↗

bioRxiv2025

Balancing Activation and Repression: CoREST-p300 Antagonism Controls Retinoic Acid-Driven Differentiation in AML

The histone demethylase KDM1A (LSD1), a component of the CoREST corepressor complex, is highly expressed in hematologic malignancies and regulates hematopoietic differentiation. Despite its essential developmental role, LSD1 inhibition has emerged as a promising strategy to enhance retinoic acid (RA)-responsive gene expression in subsets of acute myeloid leukemia (AML). Here, we show that LSD1 physically interacts with RAR/RXR heterodimers at specific genomic loci, restricting chromatin accessibility and transcriptional activation of differentiation programs. Single-agent inhibition of LSD1 or HDACs promotes only partial differentiation. In contrast, Corin, a dual LSD1/CoREST inhibitor, synergizes with all-trans retinoic acid (ATRA) to induce robust myeloid differentiation and apoptosis. Corin treatment alone does not significantly increase H3K4me3 levels; however, in combination with ATRA, it disrupts CoREST-RAR/RXR complexes and facilitates the recruitment of the coactivator p300. Together, they shift chromatin to an active state, enhancing H3K4me3 via increased transcriptional engagement and coactivator recruitment. Our findings identify the functional antagonism between CoREST and p300 as a regulatory axis of RA signaling in AML. Targeting this mechanism with Corin and ATRA re-sensitizes non-APL AML cells to RA-induced differentiation, suggesting a broader therapeutic approach for overcoming resistance in ATRA-refractory leukemias. SignificanceCo-inhibition of LSD1 and HDACs with Corin, combined with ATRA, reprograms chromatin by replacing CoREST with p300, uniquely activating differentiation-associated genes and offering a targeted strategy for treating AML. Graphical abstract created with BioRender (https://biorender.com). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/682235v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1216c81org.highwire.dtl.DTLVardef@15ac53aorg.highwire.dtl.DTLVardef@4a96d2org.highwire.dtl.DTLVardef@f3caaf_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2021

The Integrator complex regulates microRNA abundance through RISC loading

MicroRNA (miRNA) homeostasis is crucial for the post-transcriptional regulation of their target genes and miRNA dysregulation has been linked to multiple diseases, including cancer. The molecular mechanisms underlying miRNA biogenesis from processing of primary miRNA transcripts to formation of mature miRNA duplex are well understood1-4. Loading of miRNA duplex into members of the Argonaute (Ago) protein family, representing the core of the RNA-induced silencing complex (RISC), is pivotal to miRNA-mediated gene silencing5-7. The Integrator complex has been previously shown to be an important regulator of RNA maturation, RNA polymerase II pause-release, and premature transcriptional termination8-11. Here, we report that loss of Integrator results in global diminution of mature miRNAs. By incorporating 4-Thiouridine (s4U) in nascent transcripts, we traced miRNA fate from biogenesis to stabilization and identified Integrator to be essential for proper miRNA assembly into RISC. Enhanced UV crosslinking and immunoprecipitation (eCLIP) of Integrator confirms a robust association with mature miRNAs. Indeed, Integrator potentiates Ago2-mediated cleavage of target RNAs. These findings highlight an essential role for Integrator in miRNA abundance and RISC function.

molecular biology↗