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The promyelocytic leukemia PML protein is a key immune suppressor in triple-negative breast cancer

ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options and frequent resistance to immunotherapy. Here, we identify the targetable protein PML as a key mediator of immune evasion in TNBC via independent and converging mechanisms. We demonstrate that PML promotes the establishment of an immunosuppressive tumor microenvironment while concurrently impairing antigen presentation by tumor cells. Mechanistically, we find that PML partakes to the chronic activation of inflammatory and interferon-γ-responsive signaling, leading to constitutive activation of immunosuppressive genes, including PD-L1. Additionally, PML collaborates with DNMT1 to repress HLA gene expression, thus limiting tumor recognition and killing by cytotoxic T cells. Analysis of human TNBC datasets links high PML expression to impaired immune activation and poor responses to chemotherapy. As PML-targeting therapies are already clinically available for leukemia, our findings position PML as a promising actionable target to enhance immune responses and improve outcomes for patients with TNBC.

ORGANISM(S): Mus musculus

PROVIDER: GSE296217 | GEO | 2026/06/04

REPOSITORIES: GEO

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The promyelocytic leukemia PML protein is a key immune suppressor in triple-negative breast cancer [RRBS]

Project description:Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options and frequent resistance to immunotherapy. Here, we identify the targetable protein PML as a key mediator of immune evasion in TNBC via independent and converging mechanisms. We demonstrate that PML promotes the establishment of an immunosuppressive tumor microenvironment while concurrently impairing antigen presentation by tumor cells. Mechanistically, we find that PML partakes to the chronic activation of inflammatory and interferon-γ-responsive signaling, leading to constitutive activation of immunosuppressive genes, including PD-L1. Additionally, PML collaborates with DNMT1 to repress HLA gene expression, thus limiting tumor recognition and killing by cytotoxic T cells. Analysis of human TNBC datasets links high PML expression to impaired immune activation and poor responses to chemotherapy. As PML-targeting therapies are already clinically available for leukemia, our findings position PML as a promising actionable target to enhance immune responses and improve outcomes for patients with TNBC.

2026-06-04 | GSE301047 | GEO

Promyelocytic leukemia protein (PML) is a regulator of eNSC differentiation, survival and mitochondrial metabolism.

Project description:OThis study identifies the tumor suppressor PML as a regulator of embryonic neural stem cell (eNSC) homeostasis, highlighting its role in their proliferation, differentiation and metabolism. Loss of the promyelocytic leukemia (PML) protein has been previously linked to abnormal proliferation and diffentiation of embryonic neurons. Here we show that PML ablation inhibits the neuronal and oligodendrocytic lineages but favors the astrocytic pathway. A detailed analysis of the gene expression changes caused by PML loss in E13.5 NSC at both the RNA and protein level identifies several important cell pathways to be deregulated. Of note, PPARg activity, lipid and mitochondrial metabolism are down-regulated. Conversely, the mTOR and protein translation activities were upregulated. Pml-/- eNSC showed increased proliferation compared with the WT due to increased activation of the PI3K/AKT/mTOR pathway. In agreement with increased mTOR we detected reduced autophagic flux in Pml-/- cells and decreased proteasomal activity accompanied with an increase in the formation of intracellular aggregates. Functionally, Pml-/- mitochondria exhibit lower mitochondrial membrane potential, increased levels of ROS and morphological alterations. Mitochondrial defects observed in Pml-/- neural progenitors, might be attributed to reduced expression of PGC1a and impaired PPARγ signaling that can be transcriptionally and functionally restored by the action of a PPAR agonist. In summary, PML deficient NSC share commonalities with cells undergoing aging and/or neurodegeneration. Thus, we identify PML as a factor that supports neuronal survival and protects from neurotoxicity and propose that enforced PML expression may restore a compromised PPARg/PGC1A expression or function and offer therapeutic benefit.

2025-09-29 | PXD059100 | Pride

Therapy-induced PML nuclear body re-formation and p53 activation trigger acute promyelocytic leukaemia cure

Project description:The therapy-induced PML/RARA catabolism elicits the loss of APL-initiating cell self-renewal through PML NB reformation and P53 activation. These results explain the curative activity of the RA/arsenic combination, the resistance to RA of PLZF/RARA-driven APLs and they raise the prospect that activation of this PML/P53 checkpoint might have therapeutic values in other malignancies.

2014-01-11 | GSE51723 | GEO

Therapy-induced PML nuclear body re-formation and p53 activation trigger acute promyelocytic leukaemia cure

2014-01-11 | E-GEOD-51723 | biostudies-arrayexpress

PML-RARa/RXR alters the epigenetic landscape in Acute Promyelocytic Leukemia

Project description:Many different molecular mechanisms have been suggested to be associated with PML-RAR dependent transformation of haematopoietic progenitors. Here, we investigated the role of PML-RAR and RXR in the organization of epigenetic structures at a genome-wide level. We identified 2722 high confidence PML-RAR binding sites in the leukemic model cell line NB4 and found PML-RAR colocalization with RXR to the vast majority of these binding regions. Importantly, these results could be corroborated and extended in primary blast cells of two APL patients. Through genome-wide epigenetic studies we show that treatment with pharmacological doses of all-trans retinoic acid ATRA induces global alterations in active H3 acetylation and repressive H3K27me3, H3K9me3 and DNA methylation chromatin modifications. However at the PML-RAR/RXR binding sites, ATRA only induces changes in H3 acetylation. These H3 acetylation alterations triggered by the loss of PML-RAR/RXR binding affect H3 acetylation and RNA polymerase II occupancy at nearby genes. Our results suggest that PML-RAR/RXR functions as a local chromatin modulator and that specific recruitment of histone deacetylase activities to genes important for haematopoietic differentiation, RAR signaling and epigenetic control is crucial to the transforming potential of PML-RAR/RXR.

2009-12-17 | GSE18886 | GEO

PML-RARa/RXR alters the epigenetic landscape in Acute Promyelocytic Leukemia

2009-12-17 | E-GEOD-18886 | biostudies-arrayexpress

PML-RARA fusion gene requires Dnmt3a to induce acute promyelocytic leukemia in mice

Project description:Loss of function mutations in the DNA methyltransferase DNMT3A are highly recurrent in acute myeloid leukemia (AML). DNMT3A and DNMT3B encode the two methyltransferases that are primarily responsible for the de novo methylation of specific DNA sequences during cellular differentiation. DNMT3A mutations are rarely found in AML patients with translocations that create oncogenic fusion genes (e.g. PML-RARA, RUNX1-RUNX1T1, CBFB-MYH11, and MLL-X). To begin to define the reasons why these mutations do not occur together, we used retroviral vectors to express PML-RARA, RUNX1-RUNX1T1, and MLL-AF9 in the bone marrow cells of wild type (WT) or Dnmt3a deficient mice; we also examined the hematopoietic phenotypes of Ctsg-PML-RARA animals (which express PML-RARA in early hematopoietic progenitors and myeloid precursors) with and without Dnmt3a. We demonstrated that the methyltransferase activity of Dnmt3a (but not Dnmt3b) is required for aberrant self-renewal ex vivo that is driven by PML-RARA (but not RUNX1-RUNX1T1 or MLL-AF9); furthermore, the PML-RARA-driven competitive transplantation advantage and leukemia generation both required Dnmt3a. Together, these findings demonstrate that PML-RARA is specifically dependent on Dnmt3a to initiate APL in mice, and may explain why loss-of-function DNMT3A mutations are not found in patients with acute promyelocytic leukemia.

2015-10-01 | GSE68844 | GEO

Monitoring post-translational modifications and associated proteomes of WT-PML-V and two mutants from acute promyelocytic leukaemia patients refractory for arsenic therapy: A216T-PML-V and L217F-PML-V

Project description:U2OS PML-/- cells were reconstituted with YFP-PML-V of three types: WT, A216T or L217F. These cell lines were used to purify YFP-PML bodies using anti-GFP nanobody beads from cells either treated or not with arsenic (1uM for 2h). Protein samples were monitored for PML post-translational modifications and associated proteomes to try to understand why people with acute promyelocytic leukaemia that is resistant to arsenic treatment have these mutations.

2025-03-27 | PXD051743 | Pride

Promyelocytic Leukemia (PML) protein is an essential regulator of stem cell pluripotency and somatic cell reprogramming

Project description:Promyelocytic Leukemia Protein (PML) was first identified as a fusion product with the retinoic acid receptor alpha in Acute Promyelocytic Leukemia (APL). Although PML has previously been studied in cancer progression and various physiological processes, little is known about its functions in Embryonic Stem Cells (ESC). Here, we report that PML contributes to the maintenance of the ESC self-renewal by controlling the cell-cycle and sustaining the expression levels of crucial pluripotency factors. Transcriptomic analysis showed that the ablation of PML renders ESC prone to exit from the naïve and acquire a primed-like pluripotent cell state. During differentiation PML influences cell fate decision by regulation of Tbx3. PML loss compromises the reprogramming ability of embryonic fibroblasts to induced Pluripotent Stem Cells (iPSC) by inhibiting the TGFβ pathway at the very early stages. Collectively, these results designate PML as a member of the regulatory network for ESC pluripotency and somatic cell reprogramming.

2017-06-13 | GSE93922 | GEO

PML modulates epigenetic composition of chromatin to regulate expression of pro-metastatic genes in triple-negative breast cancer [ChIP-seq]

Project description:The promyelocytic leukemia (PML) protein organizes nuclear aggregates known as PML nuclear bodies (PML-NBs), where many transcription factors and transcriptional regulators converge to be regulated. Specific associations of PML and PML-NBs with chromatin are described in different cell types, further implicating PML in transcriptional regulation. However, a complete understanding of the functional consequences of PML association to DNA in a cellular context where it regulates relevant phenotypes is still lacking.We examined the role of PML in chromatin association and transcription in triple-negative breast cancer (TNBC), a pathological condition where PML exerts important oncogenic functions. We find that PML associates discontinuously with large heterochromatic PML-associated domains (PADs) that contain gene-rich euchromatic sub-domains locally depleted of PML. PML promotes heterochromatic organization in PADs and expression of pro-metastatic genes embedded in these sub-domains. Importantly, this occurs outside PML-NBs, suggesting that nucleoplasmic PML exerts a cell type-relevant function of transcriptional regulation. PML also plays an indirect regulatory function in TBNC cells by promoting the expression of pro-metastatic genes outside PADs.Our findings demonstrate that PML is an important transcriptional regulator of metastasis and pro-oncogenic metagenes in TNBC cells, via distinct molecular activities that include indirect transcriptional regulation and direct epigenetic organization of heterochromatin domains that embed regions of localized transcriptional activity.

2023-09-11 | GSE226060 | GEO

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