About

Marc Robinson is a Professor in the Practice of Dramaturgy and Dramatic Criticism at the David Geffen School of Drama. His role involves engaging with dramaturgy and dramatic criticism within the academic and theatrical community. The biography does not provide additional details about his background, research focus, or key contributions.

Research topics

• Biology
• Cell biology
• Immunology
• Genetics
• Cancer research
• Biochemistry
• Internal medicine
• Chemistry
• Medicine

Selected publications

• Dynamic feedback control of oncogenic tyrosine kinase signaling in acute leukemia

  Science Signaling · 2026-02-10

  articleOpen access

  CD25 is a subunit of the interleukin-2 (IL-2) receptor on T cells and natural killer (NK) cells. Acute leukemias with oncogenic tyrosine kinases often include CD25 + leukemia subpopulations, which portend poor clinical outcomes for patients; however, acute leukemia cells do not respond to IL-2. Here, we identified CD25 and its phosphorylation by protein kinase Cδ (PKCδ) as central elements of a feedback loop that stabilized fluctuations in oncogenic tyrosine kinase signaling in acute lymphoblastic and myeloid leukemia. Genetic ablation of CD25 in murine and patient-derived xenograft (PDX) models of acute leukemias reduced clonal fitness, colony formation, and leukemia-initiation capacity in serial transplant recipients. Oncogenic tyrosine kinase signaling in leukemia cells stimulated NF-κB–mediated CD25 expression, whereas PKCδ-mediated phosphorylation of CD25 suppressed oncogenic tyrosine kinase signaling through inhibitory phosphatases, such as PTPN6. Interactome analyses and mass spectrometry–based global phosphoproteomic analyses showed that CD25 deletion abolished the phosphatase activity of PTPN6, resulting in enhanced activation of tyrosine kinases and NF-κB. Four injections of a CD25 antibody-drug conjugate induced complete remission in mice transplanted with PDX refractory leukemia. These findings highlight the dependency of tyrosine kinase–driven leukemias on robust feedback control and the role of PKCδ and CD25 in assembling its components.

  PublisherOA PDFDOI

• Harnessing repressive LEF1/β-catenin complexes to overcome drug resistance in chronic lymphocytic leukemia

  Blood · 2025-11-03

  articleOpen access

  Abstract Background and Significance. LEF1 is overexpressed and often used as diagnostic marker for CLL. LEF1 is a transcriptional target and canonical partner of β-catenin, which acts as a transactivator of WNT/β-catenin signaling. Consistent with LEF1-expression, previous reports showed activation of β-catenin in CLL although genetic lesions stabilizing β-catenin were not found. We recently discovered that CLL express 80-200-fold lower levels of β-catenin protein than solid tumors and depend on efficient β-catenin degradation (Cosgun et al., Biorxiv 2023). Here, we identified pharmacological accumulation of β-catenin as a promising strategy for the treatment of refractory and Richter Transformation (RT) CLL. Results. To study the role of β-catenin in CLL, we introduced B-cell specific deletion of β-catenin in Eμ-Tcl1 CLL model (Mb1-Cre x Ctnnb1fl/fl). β-catenin was dispensable for CLL development and progression and CD5+ CD19+ CLL burden and survival were not changed by B-cell-specific β-catenin deletion. In a converse experiment, tamoxifen induced stabilization of β-catenin (Mb1-Cre-ERT2 x Ctnnb1ex3/+) subverted leukemogenesis: while 7 out of 11 wildtype littermates developed CLL (median survival=426 days), none of 11 mice with B-cell-specific β-catenin stabilization succumbed to CLL (P=0.02). Interestingly, β-catenin stabilization in B-cells resulted in selective depletion of CD5+ CD19+ CLL cells, which express high levels of nuclear LEF1 (intracellular FACS) and spared CD5- CD19+ normal B-cells that lack LEF1 expression. For this reason, we hypothesized that LEF1 may be mediating β-catenin induced toxicity in CLL cells. Indeed, sensitivity to GSK3B-inhibition on β-catenin accumulation strictly correlated with LEF1 expression levels (P=0.0004). In patient derived CLL cells (n=10), GSK3B-inhibition with LY2090314 mediated stabilization of β-catenin induced cell death at low nanomolar concentrations (IC50=3.5 nM). Three GSK3B inhibitors LY2090314, AZD1080 and CHIR99021 were assessed in Phase 1/2 clinical trials and achieved favorable safety and PK/PD profiles. Chemogenomic CRISPR screens for LY2090314, AZD1080 and CHIR99021 confirmed β-catenin accumulation and LEF1 expression as central mechanism of action with guide RNAs targeting CTNNB1 and LEF1 as top-ranking rescue hits. Loss of LEF1 in leukemia cells subverted nuclear translocation of β-catenin, reverted transcriptional programs induced by β-catenin activation and completely rescued β-catenin induced toxicity. Transcriptomic analysis identified that although β-catenin and LEF1 interaction led to an increase in expression of β-catenin target genes, MYC was repressed. This was surprising as in other cell types, β-catenin interacts with TCF/LEF family factors to activate MYC. CUT&RUN experiments confirmed loss of H3K27Ac signal at MYC enhancer regions upon β-catenin stabilization, which was reverted by LEF1 deletion restoring expression of MYC. Globally, β-catenin activation led to an increase of H3K27Ac signal at 10,383 regions while in 2,877 regions H3K27Ac was decreased. Further analysis of the decreased regions identified that these regions were co-bound by LEF1 and NuRD repressor components. LEF1 and β-catenin interactions led to recruitment of Nucleosome Remodeling and Deacetylase complex (NuRD), which resulted in loss of H3K27Ac signal and gene repression. Co-IP experiments using anti-β-catenin antibody confirmed interaction with LEF1, Ikaros factors and NuRD complexes in B-cell leukemia while LEF1 deletion resulted in loss of these interactions, which was particularly prominent at MYC superenhancer regions. Consistent with this model, we identified that deletion of LEF1 restored loss of H3K27Ac signal, Myc repression and rescued β-catenin mediated toxicity. Conclusions. In summary, we discovered that β-catenin is dispensable for CLL development. Unlike solid tumors and myeloid leukemias, inducible stabilization of β-catenin leads to selective elimination of CLL cells expressing high levels of LEF1. Mechanistically, LEF1 mediates nuclear translocation of β-catenin, enabling assembly of repressive complexes with NuRD factors which induce Myc repression and cell death. Three GSK3B inhibitors LY2090314, AZD1080 and CHIR99021 achieved favorable safety and PK/PD profiles in previous clinical trials for solid tumors and neurological disorders. Our results provide a rationale for repurposing GSK3B-inhibitors for the treatment of refractory and RT CLL.

  PublisherOA PDFDOI

• Alternating cycles of quiescent and proliferative cell states determine stemness and leukemia-initiation capacity in acute lymphoblastic leukemia

  Blood · 2025-11-03

  article

  Abstract Background and significance. Stemness in acute myeloid leukemia (AML) is determined by a clonal hierarchy with rare, phenotypically defined leukemia-initiating cell (LIC) at its apex (Lapidot 1994, Bonnet 1997). Given that LICs in AML are drug-resistant and initiate relapse of refractory disease, the identification of an LIC population in B-ALL would be consequential. However, unlike AML, B-ALL does not evolve from a clonal hierarchy and LIC populations have remained elusive in B-ALL (Kelly 2007, Le Viseur 2008, Rehe 2013). Results. Time-lapse studies of single patient-derived B-ALL cells revealed that most B-ALL cells were continuously proliferating (steady), while subpopulations underwent periodic transitions between quiescent and proliferative cell states (alternating). Gene expression studies of 'steady’ and 'alternating’ cells revealed a dominant and reciprocally repressive transcriptional program driven by MYC in 'steady’ and BCL6 in 'alternating’ B-ALL cells. To dissect how MYC and BCL6 dynamics govern transitions between proliferative and quiescent cell states in B-ALL, we engineered patient-derived B-ALL (PDX) by CRISPR and HDRT with dual-reporter knockin alleles expressing C-terminal MYC–mNeonGreen and BCL6–mScarletI fusion proteins. Using time-lapse imaging, we tracked MYC and BCL6 protein expression in single B-ALL cells over 20 hours. Matching their proliferative characteristics, 'steady’ B-ALL cells expressed MYC and no detectable BCL6. However, B-ALL PDX also included 'alternating’ cells that underwent multiple transitions between MYC+ BCL6- and MYC- BCL6+ cell states. PDX from BCR-ABL1 B-ALL included approximately 30% 'alternating’ cells, whereas 'alternating’ cells exceeded 50% in B-ALL PDX with RAS-pathway lesions. Among 'alternating’ cells, transitions occurred independently from cell divisions (every 36 hours) with shorter MYC-phases of three hours and longer BCL6-phases of six hours. Integrated ChIP-seq, RNA-seq, and untargeted metabolomics revealed that MYC-high cells are much larger, activated glycolysis and protein-synthesis pathways, whereas BCL6-high cells are smaller and enriched for phosphatidylethanolamine (PtdEtn) synthesis pathways. Consistent with the essential role of PtdEtn in autophagosome biogenesis, BCL6+ B-ALL cells exhibited substantially increased autophagy (LC3B flux). To directly compare MYC and BCL6 dynamics with cell growth trajectories, we combined quantitative phase microscopy and time-lapse fluorescence imaging to measure single-cell dry mass over 8 hours. Cells in the MYC-high state accumulated biomass at twice the rate of BCL6-high cells, producing a step-by-step progression of fast (MYC) and slow (BCL6) cell mass accumulation that aligned with each MYC/BCL6 state transition. Finally, multiplex immunofluorescence of FFPE biopsies from patient samples revealed spatially segregated niches of MYC-high and BCL6-high leukemia cells reminiscent of partitioning of MYC+ centrocyte and BCL6+ centroblasts in germinal centers. To experimentally induce cell state-transitions, we engineered patient-derived B-ALL cells by HDRT with dual-reporter knockin alleles expressing C-terminal MYC–dTAG fusion proteins. In addition to the MYC-dTAG degron system, we used the BCL6 PROTAC degrader ARV-393 for acute ablation of either MYC or BCL6, which was achieved within 90 minutes. Acute dTAG-mediated degradation of MYC induced cell shrinkage and decreased cellular dry mass, whereas BCL6 degradation via PROTAC decreased autophagic flux and increased dry mass, confirming opposing roles in anabolic versus catabolic metabolism. To functionally study 'steady’ (MYC-only) and 'alternating’ (MYC/BCL6) B-ALL populations, we developed a cell-sorting strategy that enriched each of the two populations to a purity of 85% as confirmed by subsequent time-lapse imaging. Extreme limiting dilution and serial transplant experiments revealed that 'steady’ (MYC-only) largely lacked LIC-capacity. In contrast, 'alternating’ (MYC/BCL6) B-ALL cells were highly enriched for LIC and initiated fatal leukemia after short latency. Conclusion: This study uncovers previously unrecognized cell state transitions in B-ALL that are controlled by MYC- and BCL6-dependent transcriptional programs. Alternating cycles of quiescent and proliferative cell states balance anabolic and catabolic metabolism, promote drug resistance, and enhance leukemia-initiating potential.

  PublisherDOI

• Abstract 2819: Metabolic determinants of ferroptosis in B-cell malignancies

  Cancer Research · 2025-04-21 · 1 citations

  article

  Abstract Although the development of targeted approaches has been effective for the treatment of B-cell malignancies, outcomes remain poor in the relapsed and refractory settings. To expand the portfolio of B-cell-selective drugs, we developed an interactive computational tool (lymphoblasts.org) and identified ferroptosis, a form of cell death driven by iron-dependent membrane lipid peroxidation, as a previously unrecognized selective vulnerability in B-cell malignancies. Although ferroptosis has shown potential in therapy-resistant tumors, no potent ferroptosis inducers are available clinically, and a better understanding of the factors regulating ferroptosis is required to allow its therapeutic targeting and the development of clinical grade ferroptosis inducers. Our comparative analyses of CRISPR dependency (DepMap) and drug (CTD, GDSC) screens revealed that B-cell malignancies are particularly sensitive to ferroptosis and depend on several anti-ferroptotic molecules that notably include components of the glutathione synthesis machinery (GCLC, GCLM, GSS) and selenoprotein synthesis (SEPHS2, LRP8). Strikingly, this analysis also identified pro-ferroptotic genes involved in iron (TFRC) and polyunsaturated fatty acid (PUFA; ACSL4) metabolism as selective B-cell dependencies, suggesting that addiction to these pro-ferroptotic processes makes B-cell malignancies intrinsically vulnerable to ferroptosis. Accordingly, iron chelation treatment showed a much higher toxicity in B-cell malignancies compared to solid tumors, and Cre-mediated ablation of Tfrc in murine models of B-cell acute lymphoblastic leukemia (B-ALL) and B-cell lymphoma induced rapid cell death. Cre-mediated loss of ACSL4, while making cells almost completely resistant to ferroptosis, significantly compromised murine B-ALL cell viability, suggesting a key role of ACSL4 and PUFA in B-cell malignancy survival. An important role of ACSL4 and PUFA metabolism in B-cell malignancies was also suggested by analysis of clinical data from the diffuse large B-cell lymphoma MMMLNP trial, which revealed that greater than median expression of ACSL4 is associated with significantly worse survival (p = 0.0007).To uncover new ferroptotic regulators in B-cell malignancies, we performed whole-genome CRISPR knockout screens under the selective pressure of the ferroptosis inducers RSL3, Erastin, and FINO2, which highlighted several known ferroptosis regulators and uncovered new ferroptosis-related genes and pathways including sphingolipid metabolism (KDSR), phosphatidylcholine synthesis (FLVCR1, PCYT1A), inositol metabolism (ITPK1, IPMK), and lipid membrane remodelling (ATP8B2). Taken together, our findings uncover iron and PUFA metabolism as selective B-cell dependencies that likely contribute to their exquisite sensitivity to ferroptosis and identifies novel regulators of ferroptosis in B-cell malignancies. Citation Format: Etienne Leveille, Eden Bramson, Mark Robinson, Thierry Bertomeu, Andrew Chatr-Aryamontri, Shalin Kothari, Markus Müschen. Metabolic determinants of ferroptosis in B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2819.

  PublisherDOI

• Ph+B-ALL is defined by BCR::ABL1-induced enhancer reprogramming and hypersensitivity to enhancer-targeting drugs

  Research Square · 2025-06-09

  preprintOpen access
  PublisherOA PDFDOI

• Single-cell transcriptomics uncovers that cell-to-cell communication controls p53 activation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-02

  preprintOpen access

  Abstract Conventional chemotherapy remains a cornerstone of cancer treatment and is highly effective in the adjuvant and neoadjuvant settings. However, therapeutic resistance, especially in the metastatic context, limits its long-term efficacy. While significant progress has been made in elucidating mechanisms of chemotherapy resistance, the role of cell-to-cell communication in modulating treatment response remains largely unexplored. Here, we combined microfluidic technology with single-cell RNA sequencing (scRNA-seq) to directly compare the transcriptional responses of cells in communication versus those in isolation. Upon dox treatment, we observed robust activation of the p53 pathway in communicating cells, whereas this response was markedly impaired in isolated cells. Moreover, pharmacological inhibition of caveolar-mediated endocytosis mimics the loss of p53 activation, further implicating this pathway in the communication-dependent regulation of chemotherapy response. This finding uncovers a previously unrecognized and essential role for paracrine signalling in mediating p53-dependent responses to chemotherapy. Our study highlights the critical importance of cell-to-cell communication in shaping therapeutic outcomes and opens new avenues for understanding and potentially overcoming chemotherapy resistance.

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• Single-cell transcriptomics uncovers that cell-to-cell communication controls p53 activation

  Research Square · 2025-07-22

  preprintOpen access
  PublisherOA PDFDOI

• Targeted hyperactivation of oncogenic STAT5-signaling in acute lymphoblastic leukemia

  Blood · 2025-11-03

  articleOpen access

  Abstract Background and Significance: Oncogenic tyrosine kinases activate STAT5a and STAT5b to promote survival and proliferation in acute lymphoblastic leukemia (B-ALL). Counterintuitively, we found that high expression levels of negative STAT5-regulators (CISH and SOCS-family proteins) predict poor clinical outcomes for B-ALL patients. Likewise, our experiments based on genetic deletion of SOCS2 and SOCS3 showed that impaired STAT5 feedback inhibition resulted in loss of colony formation and cell death in B-ALL. While STAT5 functions as oncogenic driver in B-ALL, these results highlight a previously unrecognized role of STAT5-feedback inhibition in leukemia cells and suggest a “Goldilocks zone” to maintain optimal STAT5 signaling strength. Results: To assess STAT5 signaling thresholds in vivo, we modeled modest increases and decreases of STAT5-activity based on Stat5a gain- (GOF) and loss-of-function (LOF) point mutations. Stat5aGOF B-ALL cells showed increased cell mass, glycolysis (ECAR, lactate production) and accelerated proliferation. However, increased ER-stress and cellular senescence subverted colony formation and leukemia-initiation capacity of Stat5aGOF B-ALL cells. In contrast, Stat5aLOF leukemia cells were small and quiescent with 3.5-fold increased colony formation and a 21-fold increased the frequency of leukemia-initiating cells in transplant recipients. Studying Stat5aGOF- and Stat5aLOF-dependent transcriptional programs, we identified MYC- and BCL6-target genes as top-ranking gene sets. Metabolomic analyses revealed that Stat5aGOF increased 60 MYC-dependent metabolites across glycolysis, TCA cycle and amino acid metabolism pathways. In contrast, metabolomic and lipidomic analyses revealed that Stat5aLOF promoted BCL6-dependent phosphatidylethanolamine (PtdEtn) production, which is essential for autophagosome biogenesis. Stat5aLOF not only promoted PtdEtn synthesis but also increased autophagy (LC3B puncta formation and flux). Interestingly, defective autophagy, ER-stress, and senescence in Stat5aGOF B-ALL cells were largely mitigated by supplementation of PtdEtn. To leverage MYC and BCL6 as biomarker of increased and decreased STAT5-activity, respectively, we engineered patient-derived B-ALL xenografts (PDX) with N-terminal mNeonGreen-MYC and mScarlet-BCL6 fusion knockin-alleles by CRISPR and HDRT. Single-cell time-lapse experiments over 24 hours revealed that B-ALL cells with mutant JAK2 and BCR-ABL1 autonomously transitioned between cell states of high (MYC) and low (BCL6) STAT5-activity, with a period of four hours. Interestingly, inhibitors of JAK2 (ruxolitinib) and BCR-ABL1 (imatinib) suppressed STAT5 (MYC) activity and forced transition to a quiescent BCL6+ cell state. Conversely, treatment of B-ALL PDX carrying MYC- and BCL6-knockin fusions with the STAT5-agonist ABBV-CLS-484 had the opposite effect of imatinib, strongly activated STAT5 and forced transition of BCL6+ quiescent B-ALL cells into a MYC+ proliferative cell state. To assess potential therapeutic benefit of targeted STAT5-hyperactivation, we treated NSG mice bearing patient-derived BCR-ABL1 B-ALL xenografts with daily injections of 40 mg/kg ABBV-CLS-484 i.p. for two weeks. Recapitulating the effects of Stat5aGOF in murine B-ALL, ABBV-CLS-484 treatment subverted leukemia-initiation capacity and substantially prolonged survival of transplant recipient mice. Conclusions: The tyrosine kinase inhibition paradigm is based on the dependency of B-ALL cells on high-level STAT5-signaling and activation of MYC. Our findings reveal a previously unrecognized dependency of human B-ALL cells on negative STAT5-feedback regulation by CISH and SOCS and activation of BCL6. Every four hours, B-ALL cells transition between cell-states of higher (MYC) and lower (BCL6) STAT5 activity. While traditional tyrosine kinase inhibitors target the MYC-dependent cell proliferation, our findings support a rationale for targeting BCL6-dependent quiescence. The small molecule STAT5-agonist ABBV-CLS-484 was recently introduced in Phase 2 clinical trials as immunotherapy adjuvant to increase STAT5-activity in T-cells for enhanced T-cell antitumor immunity in patients with solid tumors (NCT04777994). Since ABBV-CLS-484 showed favorable safety and desirable activation of T-cell antitumor immunity, targeted STAT5-hyperactivation is amenable to near-term evaluation in patients with refractory B-ALL.

  PublisherOA PDFDOI

• Identification of NAE1-dependent β-catenin neddylation as selective vulnerability in B-cell malignancies

  Blood · 2025-11-03

  articleOpen access

  Abstract Background and Significance. In epithelial cells, β-catenin promotes canonical WNT signaling and expression of MYC. Mutations that stabilize β-catenin protein expression function as oncogenic drivers in solid tumors and myeloid leukemia. In contrast, B-cell tumors lack activating β-catenin lesions. Despite similar mRNA levels, β-catenin protein levels in B-cell malignancies are 80- to 200-fold lower. We recently discovered that in B-cell tumors, β-catenin protein is constitutively phosphorylated by GSK3B and poised for proteasomal degradation (Cosgun et al., Biorxiv 2023). Because B-cells have evolved and critically depend on highly efficient mechanisms of β-catenin degradation, we performed genome-wide CRISPR-KO screens in β-catenin fluorescent reporter knock-in B-cell lines to identify components of this previously unrecognized B-cell-specific high-efficiency degradation complex. Results. Using HDRT, we engineered fluorescent reporter knockin alleles in B-ALL (NALM6) and mantle cell lymphoma (JEKO) cell lines for detection of β-catenin protein (mScarlet) in single living B-ALL and MCL cells. β-catenin-mScarlet signal was not visible at baseline levels. However, treatment with GSK3B inhibitor induced stabilization of β-catenin within hours, resulting in a 20-fold increase in β-catenin-mScarlet signal. We introduced iCas9 and CRISPR-KO Brunello library and sorted β-catenin-mScarlet+ cells to identify enriched guides by next generation sequencing. As expected, guides targeting classical components of the β-catenin destruction complex, APC, GSK3B, AXIN1 were strongly enriched in mScarlet+ cells. Interestingly, guides targeting the neddylation pathway, including NEDD8 activating enzyme (E1) subunits (NAE1, UBA3), NEDD8 E3 ligase (FBXW11) and NEDD8 itself were most prominently enriched in β-catenin-mScarlet+ cells, which identifies neddylation as an essential mechanism controlling β-catenin levels in B-cells. Engineering β-catenin reporter cells with single CRISPR-guides targeting NAE1, UBA3, FBXW11, and NEDD8, we validated each of these components by Western blot and flow cytometry, resulting in accumulation of β-catenin and acute cell death. Based on Nae1fl/fl mice, we generated a genetic model for inducible, Cre-mediated deletion of Nae1 in BCR-ABL1- and NRASG12D transformed murine B-ALL cells, which phenocopied CRISPR-mediated deletion in human B-ALL and MCL cells, resulting in acute cell death, loss of colony formation and leukemia initiation ability. Hematopoietic reconstitution of congenic CD45.1 mice with CD45.2 Nae1fl/fl hematopoietic progenitor cells resulted in multilineage reconstitution from CD45.2 Nae1fl/fl progenitors. Underscoring B-cell-selective activity of NAE1, acute ablation of Nae1 had no significant effect on myeloid, erythroid, NK and T-cell development but caused a near-complete block during early B-cell development at the pro- to pre-B cell transition. Translational Implications. The NAE1-inhibitors pevonedistat and TAS4464 have been studied in clinical trials hematological malignancies, including myeloid leukemia, multiple myeloma and lymphoma. However, β-catenin protein degradation was not previously considered a mechanistic target. Interestingly, publicly available compound screening data (CTD2; DepMap) revealed previously unrecognized B-cell-selectivity of both pevonedistat (P=2e-10) and TAS4465 (P=0.03). Treatment of B-cell malignancies with pevonedistat and TAS4464led to rapid accumulation of β-catenin and acute cell death at low nanomolar concentrations. Toxicity induced by NAE1-inhibitors was largely rescued by β-catenin deletion, confirming mechanism of action. Since β-catenin is phosphorylated by GSK3B, followed by neddylation and proteasomal degradation, we examined potential synergism between GSK3B- and NAE1-inhibitors. Importantly, both pevonedistat and TAS4464 strongly synergized with the GSK3B inhibitor LY2090314 in patient-derived B-ALL, mantle cell lymphoma and CLL samples. Conclusion. Based on CRISPR-screens, we discovered a novel B-cell-selective high-efficiency complex for β-catenin protein degradation, which depends on NAE1-dependent neddylation. Given the surprising B-cell-selectivity of this mechanism, our findings support a rationale to repurpose clinically tested NAE1-inhibitors for the treatment of refractory B-cell malignancies as single agent or in combination with GSK3B inhibitors.

  PublisherOA PDFDOI

• PIEZO1 Overexpression in Hereditary Hemorrhagic Telangiectasia Arteriovenous Malformations

  Circulation · 2025-07-16 · 5 citations

  articleOpen access

  BACKGROUND: Hereditary hemorrhagic telangiectasia is an inherited vascular disorder characterized by arteriovenous malformations (AVMs). Loss-of-function variations in activin receptor-like kinase 1 ( ALK1 ) cause type 2 hereditary hemorrhagic telangiectasia, and Alk1 knockout mice develop AVMs, along with overactivation of vascular endothelial growth factor receptor 2/phosphoinositide 3-kinase/AKT signaling. The full spectrum of signaling alterations resulting from ALK1 variations remains unknown, and more effective and specific inhibitors to combat AVM formation in patients are needed. METHODS: Single-cell RNA sequencing of endothelial-specific Alk1 knockout mouse retinas and controls was performed. Overexpression of fluid shear stress signaling signatures including the mechanosensitive ion channel PIEZO1 was confirmed in mouse and human type 2 hereditary hemorrhagic telangiectasia lesions. Genetic and pharmacological PIEZO1 inhibition was tested in Alk1 knockout mice, along with downstream PIEZO1 signaling. RESULTS: A cluster of Alk1 mutant endothelial cells with altered arterio-venous identity overexpressed pathways related to fluid shear stress, hypoxia, inflammation, cell cycle, and vascular endothelial growth factor receptor 2/phosphoinositide 3-kinase/AKT signaling. Piezo1 deletion and pharmacological inhibition in Alk1 -deficient mice mitigated AVM formation, whereas Piezo1 overexpression enhanced AVM formation induced by ALK1 ligand blockade. Mechanistically, PIEZO1 inhibition reduced elevated vascular endothelial growth factor receptor 2/AKT, ERK5-p62-KLF4, endothelial nitric oxide synthase, hypoxia, proliferation, and inflammation in ALK1-deficient endothelium. CONCLUSIONS: PIEZO1 expression and signaling are elevated in type 2 hereditary hemorrhagic telangiectasia. PIEZO1 blockade reduces AVM formation and alleviates cellular and molecular hallmarks of ALK1-deficient cells. This finding provides new insights into the mechanistic underpinnings of ALK1-related vascular diseases and identifies potential therapeutic targets to prevent AVMs.

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Frequent coauthors

• Markus Müschen

  Yale Cancer Center

  38 shared

• Kadriye Nehir Cosgun

  Yale University

  36 shared

• Jae Woong Lee

  Korea University

  33 shared

• Kohei Kume

  Yale University

  29 shared

• Lai N. Chan

  Yale University

  29 shared

• Anastasios Karadimitris

  Imperial College London

  23 shared

• Irene Roberts

  University of Oxford

  23 shared

• Aristeidis Chaidos

  Imperial College London

  23 shared

Labs

• Dramaturgy and Dramatic CriticismPI