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DNTTIP1 Drives Leukemogenesis Through HDAC1-Dependent Epigenetic Silencing of BMF [Cut & Tag, RS4;11 , HA-DNTTIP1]

ABSTRACT: Acute leukemia is a highly aggressive malignancy with significant unmet therapeutic needs, partly due to epigenetic dysregulation. Here, we uncover deoxynucleotidyl transferase terminal-interacting protein 1 (DNTTIP1) as a previously unrecognized epigenetic regulator crucial for the survival of leukemic cells. Mechanistically, depletion of DNTTIP1 impairs histone deacetylase 1 (HDAC1) recruitment to chromatin, leading to hyperacetylation of histone H3 lysine 27 (H3K27) at the promoter of BCL2 modifying factor (BMF) and reactivating this pro-apoptotic effector. The upregulated BMF competitively disrupts BCL2-mediated survival pathways, triggering coordinated autophagy and apoptosis. This dual cell death mechanism is critical for leukemia suppression. Our preclinical evidences demonstrate that combined HDAC1 and BCL2 inhibition exerts synergistic anti-leukemic effects, a therapeutic strategy currently under clinical evaluation. Furthermore, we demonstrate that PARP inhibitors profoundly synergize with HDAC1/BCL2 inhibition through interference with DNA damage repair, creating a novel three-pronged therapeutic strategy. Our findings identifies the DNTTIP1-HDAC1-BMF axis as a pivotal epigenetic vulnerability in acute leukemia and reveal its functional roles in sustaining leukemogenesis. This work offers a validated biological framework for advancing this targeted combination therapy into clinical trials.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305431 | GEO | 2026/03/12

REPOSITORIES: GEO

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DNTTIP1 Drives Leukemogenesis Through HDAC1-Dependent Epigenetic Silencing of BMF [Cut & Tag, RS4;11]

Project description:Acute leukemia is a highly aggressive malignancy with significant unmet therapeutic needs, partly due to epigenetic dysregulation. Here, we uncover deoxynucleotidyl transferase terminal-interacting protein 1 (DNTTIP1) as a previously unrecognized epigenetic regulator crucial for the survival of leukemic cells. Mechanistically, depletion of DNTTIP1 impairs histone deacetylase 1 (HDAC1) recruitment to chromatin, leading to hyperacetylation of histone H3 lysine 27 (H3K27) at the promoter of BCL2 modifying factor (BMF) and reactivating this pro-apoptotic effector. The upregulated BMF competitively disrupts BCL2-mediated survival pathways, triggering coordinated autophagy and apoptosis. This dual cell death mechanism is critical for leukemia suppression. Our preclinical evidences demonstrate that combined HDAC1 and BCL2 inhibition exerts synergistic anti-leukemic effects, a therapeutic strategy currently under clinical evaluation. Furthermore, we demonstrate that PARP inhibitors profoundly synergize with HDAC1/BCL2 inhibition through interference with DNA damage repair, creating a novel three-pronged therapeutic strategy. Our findings identifies the DNTTIP1-HDAC1-BMF axis as a pivotal epigenetic vulnerability in acute leukemia and reveal its functional roles in sustaining leukemogenesis. This work offers a validated biological framework for advancing this targeted combination therapy into clinical trials.

2026-03-12 | GSE305430 | GEO

DNTTIP1 Drives Leukemogenesis Through HDAC1-Dependent Epigenetic Silencing of BMF [ATAC-Seq]

2026-03-12 | GSE305428 | GEO

DNTTIP1 Drives Leukemogenesis Through HDAC1-Dependent Epigenetic Silencing of BMF [RNA-Seq, 2]

2026-03-12 | GSE305437 | GEO

DNTTIP1 Drives Leukemogenesis Through HDAC1-Dependent Epigenetic Silencing of BMF [RNA-Seq, 1]

2026-03-12 | GSE305435 | GEO

Embryonic day 13.5 mRNA profiles for wildtype and MIDEAS and DNTTIP1 knockout MEFs

Project description:Objective: Perform deep sequencing on mouse embryonic fibroblasts from e13.5 embryos with wildtype, MIDEAS-/- and DNTTIP1-/- genotypes to provide insights into observed embryonic lethality with associated haemolytic anaemia and heart defects. Method: Heterozygous mates of MIDEAS or DNTTIP1 set up and pregnant females culled at e13.5. MEFs were created from embryos and cultured for 4-6 passages before total RNA extraction and deep sequencing (novogene) to obtain mRNA pofiles. FastQ files processed using TRIMGALORE!, STAR, Picards remove duplicates and SAM Tools. R was used for DESeq2 analysis to find differentially regulated genes Results: A large number of both up and down regulated genes were found for both MIDEAS and DNTTIP1 knockout MEFs compared to wildtype. Of these a significant amount were common to both knockouts suggesting a role in the same complex and shared gene targets. A number of these transcripts were associated with angiogenesis and haematopoiesis as well as neual development. Conclusion: Whilst further biological experiments are required to confirm reason for haemolytic anaemia present in knockout embryos there is a strong indication this could be caused by changes in gene regulation cause by the loss of the MIDAC compex

2020-05-26 | GSE144748 | GEO

The transcription factor IRF4 represses pro-apoptotic BMF and BIM to licence Multiple Myeloma survival

Project description:The transcription factor Interferon Regulatory Factor 4 (IRF4) is essential for the survival of the plasma cell malignancy multiple myeloma (MM), although the mechanism by which this is achieved remains unknown. Here we have explored the genetic basis for IRF4 addiction through CRISPR-Cas9 genetic ablation of IRF4 across several MM cells lines. We report that IRF4 loss uniformly resulted in the upregulation of two related pro-apoptotic proteins belonging to the BH3-only subgroup of the BCL2 family: BCL2 modifying factor (BMF) and BCL2 interacting mediator of cell death (BIM). Direct IRF4 binding was identified in the proximal promoter region of both genes. Remarkably, genetic ablation of BMF alone or in combination with BIM largely prevented the cell death that follows IRF4 inactivation, establishing that IRF4 maintains MM survival through the direct transcriptional repression of BMF and BIM.

2022-12-22 | GSE148984 | GEO

A Generalized Strategy to Kill Leukemic Cells by Targeting the Regulatory Systems Governing Mitochondrial Membrane Potential

Project description:Targeting mitochondria emerges as a promising anti-leukemia strategy, yet selective mitochondrial disruption remains challenging. Here, we identified elevated mitochondrial membrane potential (MMP) as a hallmark of leukemic transformation and chemotherapy-resistant cells, prompting screening for MMP-targeting agents. Alexidine, an MMP-depleting compound, demonstrated potent anti-leukemic activity with low toxicity. Mechanistically, Alexidine binds unsaturated cardiolipin to destabilize the inner membrane localization of mitochondrial ribosome, suppressing cardiolipin-dependent mitochondrial translation, a process validated as an independent prognostic marker in leukemia. Unlike chemotherapy, Alexidine eradicates baseline MMP and MMP heterogeneity within leukemic populations, a functional signature linked to stemness and chemoresistance. Intriguingly, this heterogeneity originates not from cardiolipin-mediated translation but from asparagine-driven mitochondrial protein synthesis, which leukemia cells selectively activate to bypass chemotherapy. Critically, pharmacological asparagine depletion synergistically enhances chemosensitivity by disrupting this resistance pathway. Our findings establish that MMP regulation through cardiolipin-maintained homeostasis and asparagine-fueled adaptation represents therapeutic vulnerabilities, advocating co-targeting strategies to overcome resistance.

2025-07-11 | MTBLS12596 | MetaboLights

Dosage dependent tumor suppression by histone deacetylase 1 and 2 by regulation of Myc collaborating genes and p53 function

Project description:comparative genome hybridisation of Hdac1/2 cKO lymphomas and matched normal tissue Histone deacetylases (HDACs) are epigenetic erasers of lysine-acetyl marks. Inhibition of HDACs using small molecule inhibitors (HDACi) is a potential strategy in the treatment of various diseases and is approved for treating hematological malignancies. Harnessing the therapeutic potential of HDACi requires knowledge of HDAC-function in vivo. Here, we generated a thymocyte-specific gradient of HDAC-activity using compound conditional knockout mice for Hdac1 and Hdac2. Unexpectedly, gradual loss of HDAC-activity engendered a dosage dependent accumulation of immature thymocytes and correlated with the incidence and latency of monoclonal lymphoblastic thymic lymphomas. Strikingly, complete ablation of Hdac1 and Hdac2 abrogated lymphomagenesis due to a block in early thymic development. Genomic, biochemical and functional analyses of pre-leukemic thymocytes and tumors revealed a critical role for Hdac1/Hdac2-governed HDAC-activity in regulating a p53-dependent barrier to constrain Myc-overexpressing thymocytes from progressing into lymphomas by regulating Myc-collaborating genes. One Myc-collaborating and p53-suppressing gene, Jdp2, was derepressed in an Hdac1/2-dependent manner and critical for the survival of Jdp2-overexpressing lymphoma cells. Although reduced HDAC-activity facilitates oncogenic transformation in normal cells, resulting tumor cells remain highly dependent on HDAC-activity, indicating that a critical level of Hdac1 and Hdac2 governed HDAC-activity is required for tumor maintenance. genomic DNA from LckCre+;Hdac1/2 cKO lymphomas and matched normal genomic DNA was hybridized onto a Nimblegen whole genome array

2013-01-11 | E-GEOD-43407 | biostudies-arrayexpress

Targeting epigenetic networks mediated by Prmt1 and Kdm4c in acute myeloid leukemia

Project description:Transcriptional deregulation plays a major role in acute myeloid leukemia, identification of epigenetic modifying enzymes essential for the maintenance of oncogenic transcription programs holds the key to better understanding the biology and designing effective therapeutic strategies for the disease. Here we provide experimental evidence showing the functional involvement and therapeutic potentials of targeting PRMT1 with H4R3 methyltransferase activity in various MLL and non-MLL leukemias. PRMT1 is necessary but not sufficient for leukemic transformation, which requires co-recruitment of KDM4C with H3K9 demethylase activity by chimeric transcription factors to mediate epigenetic reprogramming. Inhibition of KDM4C/PRMT1 suppresses transcription and transformation ability of MLL fusions and MOZ-TIF2, revealing a novel and targetable epigenetic circuitry mediated by PRMT1 and KDM4C in acute leukemia.

2016-01-14 | E-MTAB-3322 | biostudies-arrayexpress

Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones

Project description:Understanding the contribution of abnormal genetic and epigenetic programs to acute myeloid leukemia (AML) is necessary for the integrated design of targeted therapies. To investigate this, we determined the effect of epigenetic reprogramming on leukemic behavior by generating induced pluripotent stem cells (iPSCs) from AML patient samples harboring MLL rearrangements. AML-derived iPSCs (AML-iPSCs) retained leukemic mutations, but reset leukemic DNA methylation/gene expression patterns and lacked leukemic potential. However, when differentiated into hematopoietic cells, AML-iPSCs reacquired the ability to give rise to leukemia in vivo and reestablished leukemic methylation/gene expression patterns, including an aberrant MLL signature, indicating that epigenetic reprogramming was insufficient to eliminate leukemic behavior. In one case, we identified distinct AML-iPSC KRAS mutant and wildtype subclones that demonstrated differential growth properties and therapeutic susceptibilities, predicting KRAS wildtype clonal relapse due to increased cytarabine resistance. Increased cytarabine resistance was further observed in a cohort of KRAS wildtype MLL-rearranged AML samples, demonstrating the utility of AML-iPSCs in predicting subclonal relapse and facilitating clonal targeting in AML. This SuperSeries is composed of the SubSeries listed below.

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