Anja Deutzmann

All Publications

• MYC-driven synthesis of Siglec ligands is a glycoimmune checkpoint. Proceedings of the National Academy of Sciences of the United States of America Smith, B. A., Deutzmann, A., Correa, K. M., Delaveris, C. S., Dhanasekaran, R., Dove, C. G., Sullivan, D. K., Wisnovsky, S., Stark, J. C., Pluvinage, J. V., Swaminathan, S., Riley, N. M., Rajan, A., Majeti, R., Felsher, D. W., Bertozzi, C. R. 2023; 120 (11): e2215376120

  Abstract

  The Siglecs (sialic acid-binding immunoglobulin-like lectins) are glycoimmune checkpoint receptors that suppress immune cell activation upon engagement of cognate sialoglycan ligands. The cellular drivers underlying Siglec ligand production on cancer cells are poorly understood. We find the MYC oncogene causally regulates Siglec ligand production to enable tumor immune evasion. A combination of glycomics and RNA-sequencing of mouse tumors revealed the MYC oncogene controls expression of the sialyltransferase St6galnac4 and induces a glycan known as disialyl-T. Using in vivo models and primary human leukemias, we find that disialyl-T functions as a "don't eat me" signal by engaging macrophage Siglec-E in mice or the human ortholog Siglec-7, thereby preventing cancer cell clearance. Combined high expression of MYC and ST6GALNAC4 identifies patients with high-risk cancers and reduced tumor myeloid infiltration. MYC therefore regulates glycosylation to enable tumor immune evasion. We conclude that disialyl-T is a glycoimmune checkpoint ligand. Thus, disialyl-T is a candidate for antibody-based checkpoint blockade, and the disialyl-T synthase ST6GALNAC4 is a potential enzyme target for small molecule-mediated immune therapy.

  View details for DOI 10.1073/pnas.2215376120

  View details for PubMedID 36897988

• MYC oncogene elicits tumorigenesis associated with embryonic, ribosomal biogenesis, and tissue-lineage dedifferentiation gene expression changes. Oncogene Sullivan, D. K., Deutzmann, A., Yarbrough, J., Krishnan, M. S., Gouw, A. M., Bellovin, D. I., Adam, S. J., Liefwalker, D. F., Dhanasekaran, R., Felsher, D. W. 2022

  Abstract

  MYC is a transcription factor frequently overexpressed in cancer. To determine how MYC drives the neoplastic phenotype, we performed transcriptomic analysis using a panel of MYC-driven autochthonous transgenic mouse models. We found that MYC elicited gene expression changes mostly in a tissue- and lineage-specific manner across B-cell lymphoma, T-cell acute lymphoblastic lymphoma, hepatocellular carcinoma, renal cell carcinoma, and lung adenocarcinoma. However, despite these gene expression changes being mostly tissue-specific, we uncovered a convergence on a common pattern of upregulation of embryonic stem cell gene programs and downregulation of tissue-of-origin gene programs across MYC-driven cancers. These changes are representative of lineage dedifferentiation, that may be facilitated by epigenetic alterations that occur during tumorigenesis. Moreover, while several cellular processes are represented among embryonic stem cell genes, ribosome biogenesis is most specifically associated with MYC expression in human primary cancers. Altogether, MYC's capability to drive tumorigenesis in diverse tissue types appears to be related to its ability to both drive a core signature of embryonic genes that includes ribosomal biogenesis genes as well as promote tissue and lineage specific dedifferentiation.

  View details for DOI 10.1038/s41388-022-02458-9

  View details for PubMedID 36207533

• The MYC oncogene - the grand orchestrator of cancer growth and immune evasion. Nature reviews. Clinical oncology Dhanasekaran, R., Deutzmann, A., Mahauad-Fernandez, W. D., Hansen, A. S., Gouw, A. M., Felsher, D. W. 2021

  Abstract

  The MYC proto-oncogenes encode a family of transcription factors that are among the most commonly activated oncoproteins in human neoplasias. Indeed, MYC aberrations or upregulation of MYC-related pathways by alternate mechanisms occur in the vast majority of cancers. MYC proteins are master regulators of cellular programmes. Thus, cancers with MYC activation elicit many of the hallmarks of cancer required for autonomous neoplastic growth. In preclinical models, MYC inactivation can result in sustained tumour regression, a phenomenon that has been attributed to oncogene addiction. Many therapeutic agents that directly target MYC are under development; however, to date, their clinical efficacy remains to be demonstrated. In the past few years, studies have demonstrated that MYC signalling can enable tumour cells to dysregulate their microenvironment and evade the host immune response. Herein, we discuss how MYC pathways not only dictate cancer cell pathophysiology but also suppress the host immune response against that cancer. We also propose that therapies targeting the MYC pathway will be key to reversing cancerous growth and restoring antitumour immune responses in patients with MYC-driven cancers.

  View details for DOI 10.1038/s41571-021-00549-2

  View details for PubMedID 34508258

• MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies. Nature communications Swaminathan, S., Hansen, A. S., Heftdal, L. D., Dhanasekaran, R., Deutzmann, A., Fernandez, W. D., Liefwalker, D. F., Horton, C., Mosley, A., Liebersbach, M., Maecker, H. T., Felsher, D. W. 2020; 11 (1): 2860

  Abstract

  The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt's lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRalpha-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYCON T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.

  View details for DOI 10.1038/s41467-020-16447-7

  View details for PubMedID 32503978

• Spontaneous Regression of HCC- When the Immune System Stands Up to Cancer. Hepatology (Baltimore, Md.) Arjunan, V. n., Hansen, A. n., Deutzmann, A. n., Sze, D. Y., Dhanasekaran, R. n. 2020

  Abstract

  Spontaneous regression of cancer is rare and has been observed mostly in immunogenic cancers like melanoma. A few cases of spontaneous regression of hepatocellular carcinoma (HCC) have been reported, but the mechanisms of regression have not been elucidated. Here, we report a patient with advanced HCC who experienced spontaneous regression of her tumor and present evidence for a putative immune-mediated mechanism for tumor regression.

  View details for DOI 10.1002/hep.31489

  View details for PubMedID 32740961

• Stabilization of the Max Homodimer with a Small Molecule Attenuates Myc-Driven Transcription. Cell chemical biology Struntz, N. B., Chen, A., Deutzmann, A., Wilson, R. M., Stefan, E., Evans, H. L., Ramirez, M. A., Liang, T., Caballero, F., Wildschut, M. H., Neel, D. V., Freeman, D. B., Pop, M. S., McConkey, M., Muller, S., Curtin, B. H., Tseng, H., Frombach, K. R., Butty, V. L., Levine, S. S., Feau, C., Elmiligy, S., Hong, J. A., Lewis, T. A., Vetere, A., Clemons, P. A., Malstrom, S. E., Ebert, B. L., Lin, C. Y., Felsher, D. W., Koehler, A. N. 2019

  Abstract

  The transcription factor Max is a basic-helix-loop-helix leucine zipper (bHLHLZ) protein that forms homodimers or interacts with other bHLHLZ proteins, including Myc and Mxd proteins. Among this dynamic network of interactions, the Myc/Max heterodimer has crucial roles in regulating normal cellular processes, but its transcriptional activity is deregulated in a majority of human cancers. Despite this significance, the arsenal of high-quality chemical probes to interrogate these proteins remains limited. We used small molecule microarrays to identify compounds that bind Max in a mechanistically unbiased manner. We discovered the asymmetric polycyclic lactam, KI-MS2-008, which stabilizes the Max homodimer while reducing Myc protein and Myc-regulated transcript levels. KI-MS2-008 also decreases viable cancer cell growth in a Myc-dependent manner and suppressestumor growth invivo. This approach demonstrates the feasibility of modulating Max with small molecules and supports altering Max dimerization as an alternative approach to targeting Myc.

  View details for DOI 10.1016/j.chembiol.2019.02.009

  View details for PubMedID 30880155

• Mebendazole for Differentiation Therapy of Acute Myeloid Leukemia Identified by a Lineage Maturation Index. Scientific reports Li, Y. n., Thomas, D. n., Deutzmann, A. n., Majeti, R. n., Felsher, D. W., Dill, D. L. 2019; 9 (1): 16775

  Abstract

  Accurate assessment of changes in cellular differentiation status in response to drug treatments or genetic perturbations is crucial for understanding tumorigenesis and developing novel therapeutics for human cancer. We have developed a novel computational approach, the Lineage Maturation Index (LMI), to define the changes in differentiation state of hematopoietic malignancies based on their gene expression profiles. We have confirmed that the LMI approach can detect known changes of differentiation state in both normal and malignant hematopoietic cells. To discover novel differentiation therapies, we applied this approach to analyze the gene expression profiles of HL-60 leukemia cells treated with a small molecule drug library. Among multiple drugs that significantly increased the LMIs, we identified mebendazole, an anti-helminthic clinically used for decades with no known significant toxicity. We tested the differentiation activity of mebendazole using primary leukemia blast cells isolated from human acute myeloid leukemia (AML) patients. We determined that treatment with mebendazole induces dramatic differentiation of leukemia blast cells as shown by cellular morphology and cell surface markers. Furthermore, mebendazole treatment significantly extended the survival of leukemia-bearing mice in a xenograft model. These findings suggest that mebendazole may be utilized as a low toxicity therapeutic for human acute myeloid leukemia and confirm the LMI approach as a robust tool for the discovery of novel differentiation therapies for cancer.

  View details for DOI 10.1038/s41598-019-53290-3

  View details for PubMedID 31727951

• MYC Functions As a Master Switch for Natural Killer Cell-Mediated Immune Surveillance of Lymphoid Malignancies Swaminathan, S., Heftdal, L., Liefwalker, D. F., Dhanasekaran, R., Deutzmann, A., Horton, C., Mosley, A., Liebersbach, M., Maecker, H. T., Felsher, D. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-110472

  View details for Web of Science ID 000454837607225

• BIM-mediated apoptosis and oncogene addiction. Aging Li, Y., Deutzmann, A., Felsher, D. W. 2016; 8 (9): 1834-1835

  View details for DOI 10.18632/aging.101072

  View details for PubMedID 27688082

  View details for PubMedCentralID PMC5076438

• BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia ONCOTARGET Li, Y., Deutzmann, A., Choi, P. S., Fan, A. C., Felsher, D. W. 2016; 7 (19): 26926-26934

  Abstract

  Oncogene inactivation in both clinical targeted therapies and conditional transgenic mouse cancer models can induce significant tumor regression associated with the robust induction of apoptosis. Here we report that in MYC-, RAS-, and BCR-ABL-induced acute lymphoblastic leukemia (ALL), apoptosis upon oncogene inactivation is mediated by the same pro-apoptotic protein, BIM. The induction of BIMin the MYC- and RAS-driven leukemia is mediated by the downregulation of miR-17-92. Overexpression of miR-17-92 blocked the induction of apoptosis upon oncogene inactivation in the MYC and RAS-driven but not in the BCR-ABL-driven ALL leukemia. Hence, our results provide novel insight into the mechanism of apoptosis upon oncogene inactivation and suggest that induction of BIM-mediated apoptosis may be an important therapeutic approach for ALL.

  View details for DOI 10.18632/oncotarget.8731

  View details for Web of Science ID 000377741700001

• BIM mediates oncogene inactivation-induced apoptosis in multiple transgenic mouse models of acute lymphoblastic leukemia. Oncotarget Li, Y., Deutzmann, A., Choi, P. S., Fan, A. C., Felsher, D. W. 2016

  Abstract

  Oncogene inactivation in both clinical targeted therapies and conditional transgenic mouse cancer models can induce significant tumor regression associated with the robust induction of apoptosis. Here we report that in MYC-, RAS-, and BCR-ABL-induced acute lymphoblastic leukemia (ALL), apoptosis upon oncogene inactivation is mediated by the same pro-apoptotic protein, BIM. The induction of BIMin the MYC- and RAS-driven leukemia is mediated by the downregulation of miR-17-92. Overexpression of miR-17-92 blocked the induction of apoptosis upon oncogene inactivation in the MYC and RAS-driven but not in the BCR-ABL-driven ALL leukemia. Hence, our results provide novel insight into the mechanism of apoptosis upon oncogene inactivation and suggest that induction of BIM-mediated apoptosis may be an important therapeutic approach for ALL.

  View details for DOI 10.18632/oncotarget.8731

  View details for PubMedID 27095570

• The human oncoprotein and chromatin architectural factor DEK counteracts DNA replication stress ONCOGENE Deutzmann, A., Ganz, M., Schoenenberger, F., Vervoorts, J., Kappes, F., Ferrando-May, E. 2015; 34 (32): 4270–77

  Abstract

  DNA replication stress is a major source of DNA strand breaks and genomic instability, and a hallmark of precancerous lesions. In these hyperproliferative tissues, activation of the DNA damage response results in apoptosis or senescence preventing or delaying their development to full malignancy. In cells, in which this antitumor barrier is disabled by mutations (for example, in p53), viability and further uncontrolled proliferation depend on factors that help to cope with replication-associated DNA damage. Replication problems preferentially arise in chromatin regions harboring complex DNA structures. DEK is a unique chromatin architectural factor which binds to non-B-form DNA structures, such as cruciform DNA or four-way junctions. It regulates DNA topology and chromatin organization, and is essential for the maintenance of heterochromatin integrity. Since its isolation as part of an oncogenic fusion in a subtype of AML, DEK has been consistently associated with tumor progression and chemoresistance. How DEK promotes cancer, however, is poorly understood. Here we show that DEK facilitates cellular proliferation under conditions of DNA replication stress by promoting replication fork progression. DEK also protects from the transmission of DNA damage to the daughter cell generation. We propose that DEK counteracts replication stress and ensures proliferative advantage by resolving problematic DNA and/or chromatin structures at the replication fork.

  View details for DOI 10.1038/onc.2014.346

  View details for Web of Science ID 000359199800013

  View details for PubMedID 25347734

• Discrimination of cell cycle phases in PCNA-immunolabeled cells. BMC bioinformatics Schönenberger, F., Deutzmann, A., Ferrando-May, E., Merhof, D. 2015; 16: 180-?

  Abstract

  Protein function in eukaryotic cells is often controlled in a cell cycle-dependent manner. Therefore, the correct assignment of cellular phenotypes to cell cycle phases is a crucial task in cell biology research. Nuclear proteins whose localization varies during the cell cycle are valuable and frequently used markers of cell cycle progression. Proliferating cell nuclear antigen (PCNA) is a protein which is involved in DNA replication and has cell cycle dependent properties. In this work, we present a tool to identify cell cycle phases and in particular, sub-stages of the DNA replication phase (S-phase) based on the characteristic patterns of PCNA distribution. Single time point images of PCNA-immunolabeled cells are acquired using confocal and widefield fluorescence microscopy. In order to discriminate different cell cycle phases, an optimized processing pipeline is proposed. For this purpose, we provide an in-depth analysis and selection of appropriate features for classification, an in-depth evaluation of different classification algorithms, as well as a comparative analysis of classification performance achieved with confocal versus widefield microscopy images.We show that the proposed processing chain is capable of automatically classifying cell cycle phases in PCNA-immunolabeled cells from single time point images, independently of the technique of image acquisition. Comparison of confocal and widefield images showed that for the proposed approach, the overall classification accuracy is slightly higher for confocal microscopy images.Overall, automated identification of cell cycle phases and in particular, sub-stages of the DNA replication phase (S-phase) based on the characteristic patterns of PCNA distribution, is feasible for both confocal and widefield images.

  View details for DOI 10.1186/s12859-015-0618-9

  View details for PubMedID 26022740

  View details for PubMedCentralID PMC4448323

• Imaging of the DNA damage-induced dynamics of nuclear proteins via nonlinear photoperturbation JOURNAL OF BIOPHOTONICS Tomas, M., Blumhardt, P., Deutzmann, A., Schwarz, T., Kromm, D., Leitenstorfer, A., Ferrando-May, E. 2013; 6 (8): 645–55

  Abstract

  Understanding the cellular response to DNA strand breaks is crucial to decipher the mechanisms maintaining the integrity of our genome. We present a novel method to visualize how the mobility of nuclear proteins changes in response to localized DNA damage. DNA strand breaks are induced via nonlinear excitation with femtosecond laser pulses at λ = 1050 nm in a 3D-confined subnuclear volume. After a time delay of choice, protein mobility within this volume is analysed by two-photon photoactivation of PA-GFP fusion proteins at λ = 775 nm. By changing the position of the photoactivation spot with respect to the zone of lesion the influence of chromatin structure and of the distance from damage are investigated. As first applications we demonstrate a locally confined, time-dependent mobility increase of histone H1.2, and a progressive retardation of the DNA repair factor XRCC1 at damaged sites. This assay can be used to map the response of nuclear proteins to DNA damage in time and space.

  View details for DOI 10.1002/jbio.201200170

  View details for Web of Science ID 000327705800009

  View details for PubMedID 23420601

• Intercellular trafficking of the nuclear oncoprotein DEK PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Saha, A. K., Kappes, F., Mundade, A., Deutzmann, A., Rosmarin, D. M., Legendre, M., Chatain, N., Al-Obaidi, Z., Adams, B. S., Ploegh, H. L., Ferrando-May, E., Mor-Vaknin, N., Markovitz, D. M. 2013; 110 (17): 6847–52

  Abstract

  DEK is a biochemically distinct, conserved nonhistone protein that is vital to global heterochromatin integrity. In addition, DEK can be secreted and function as a chemotactic, proinflammatory factor. Here we show that exogenous DEK can penetrate cells, translocate to the nucleus, and there carry out its endogenous nuclear functions. Strikingly, adjacent cells can take up DEK secreted from synovial macrophages. DEK internalization is a heparan sulfate-dependent process, and cellular uptake of DEK into DEK knockdown cells corrects global heterochromatin depletion and DNA repair deficits, the phenotypic aberrations characteristic of these cells. These findings thus unify the extracellular and intracellular activities of DEK, and suggest that this paracrine loop involving DEK plays a role in chromatin biology.

  View details for DOI 10.1073/pnas.1220751110

  View details for Web of Science ID 000318677300058

  View details for PubMedID 23569252

  View details for PubMedCentralID PMC3637753

• Chromatin Composition Is Changed by Poly(ADP-ribosyl)ation during Chromatin Immunoprecipitation PLOS ONE Beneke, S., Meyer, K., Holtz, A., Huettner, K., Buerkle, A. 2012; 7 (3): e32914

  Abstract

  Chromatin-immunoprecipitation (ChIP) employs generally a mild formaldehyde cross-linking step, which is followed by isolation of specific protein-DNA complexes and subsequent PCR testing, to analyze DNA-protein interactions. Poly(ADP-ribosyl)ation, a posttranslational modification involved in diverse cellular functions like repair, replication, transcription, and cell death regulation, is most prominent after DNA damage. Poly(ADP-ribose)polymerase-1 is activated upon binding to DNA strand-breaks and coordinates repair by recruitment or displacement of proteins. Several proteins involved in different nuclear pathways are directly modified or contain poly(ADP-ribose)-interaction motifs. Thus, poly(ADP-ribose) regulates chromatin composition. In immunofluorescence experiments, we noticed artificial polymer-formation after formaldehyde-fixation of undamaged cells. Therefore, we analyzed if the formaldehyde applied during ChIP also induces poly(ADP-ribosyl)ation and its impact on chromatin composition. We observed massive polymer-formation in three different ChIP-protocols tested independent on the cell line. This was due to induction of DNA damage signaling as monitored by γH2AX formation. To abrogate poly(ADP-ribose) synthesis, we inhibited this enzymatic reaction either pharmacologically or by increased formaldehyde concentration. Both approaches changed ChIP-efficiency. Additionally, we detected specific differences in promoter-occupancy of tested transcription factors as well as the in the presence of histone H1 at the respective sites. In summary, we show here that standard ChIP is flawed by artificial formation of poly(ADP-ribose) and suppression of this enzymatic activity improves ChIP-efficiency in general. Also, we detected specific changes in promoter-occupancy dependent on poly(ADP-ribose). By preventing polymer synthesis with the proposed modifications in standard ChIP protocols it is now possible to analyze the natural chromatin-composition.

  View details for DOI 10.1371/journal.pone.0032914

  View details for Web of Science ID 000305339100024

  View details for PubMedID 22479348

  View details for PubMedCentralID PMC3316553