Benjamin Rolles

All Publications

• Inherited Telomere Biology Disorders: Pathophysiology, Clinical Presentation, Diagnostics, and Treatment. Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie Rolles, B., Tometten, M., Meyer, R., Kirschner, M., Beier, F., Brümmendorf, T. H. 2024; 51 (5): 292-309

  Abstract

  Telomeres are the end-capping structures of all eukaryotic chromosomes thereby protecting the genome from damage and degradation. During the aging process, telomeres shorten continuously with each cell division until critically short telomeres prevent further proliferation whereby cells undergo terminal differentiation, senescence, or apoptosis. Premature aging due to critically short telomere length (TL) can also result from pathogenic germline variants in the telomerase complex or related genes that typically counteract replicative telomere shortening in germline and certain somatic cell populations, e.g., hematopoetic stem cells. Inherited diseases that result in altered telomere maintenance are summarized under the term telomere biology disorder (TBD).Since TL both reflects but more importantly restricts the replicative capacity of various human tissues, a sufficient telomere reserve is particularly important in cells with high proliferative activity (e.g., hematopoiesis, immune cells, intestinal cells, liver, lung, and skin). Consequently, altered telomere maintenance as observed in TBDs typically results in premature replicative cellular exhaustion in the respective organ systems eventually leading to life-threatening complications such as bone marrow failure (BMF), pulmonary fibrosis, and liver cirrhosis.The recognition of a potential congenital origin in approximately 10% of adult patients with clinical BMF is of utmost importance for the proper diagnosis, appropriate patient and family counseling, to prevent the use of inefficient treatment and to avoid therapy-related toxicities including appropriate donor selection when patients have to undergo stem cell transplantation from related donors. This review summarizes the current state of knowledge about TBDs with particular focus on the clinical manifestation patterns in children (termed early onset TBD) compared to adults (late-onset TBD) including typical treatment- and disease course-related complications as well as their prognosis and adequate therapy. Thereby, it aims to raise awareness for a disease group that is currently still highly underdiagnosed particularly when it first manifests itself in adulthood.

  View details for DOI 10.1159/000540109

  View details for PubMedID 39371255

  View details for PubMedCentralID PMC11452174

• Leukemia cells accumulate zinc for oncofusion protein stabilization. The Journal of nutritional biochemistry Görg, R., Büttgenbach, A., Jakobs, J., Kurtoğlu Babayev, F. H., Rolles, B., Rink, L., Wessels, I. 2024; 123: 109482

  Abstract

  Acute promyelocytic leukemia (APL) and chronic myeloid leukemia (CML) are both hematological malignancies characterized by genetic alterations leading to the formation of oncofusion proteins. The classical chromosomal aberrations in APL and CML result in the PML-RARα and BCR-ABL1 oncofusion proteins, respectively. Interestingly, our flow cytometric analyses revealed elevated free intracellular zinc levels in various leukemia cells, which may play a role in stabilizing oncofusion proteins in leukemia and thus support cell proliferation and malignancy. Long-term zinc deficiency resulted in the degradation of PML-RARα in NB4 cells (APL cell line) and of BCR-ABL1 in K562 cells (CML cell line). This degradation may be explained by increased caspase 3 activity observed in zinc deficient cells, whereas zinc reconstitution normalized the caspase 3 activity and abolished zinc deficiency-induced oncofusion protein degradation. In NB4 cells, fluorescence microscopic images further indicated enlarged and enriched lysosomes during zinc deficiency, suggesting increased rates of autophagy. Moreover, NB4 cells exhibited increased expression of the zinc transporters ZIP2, ZIP10 and ZnT3 during zinc deficiency and revealed excessive accumulation of zinc in contrast to healthy peripheral blood mononuclear cells (PBMCs), when zinc was abundantly available extracellularly. Our results highlight the importance of altered zinc homeostasis for some characteristics in leukemia cells, uncover potential pathways underlying the effects of zinc deficiency in leukemia cells, and provide potential alternative strategies by which oncofusion proteins can be degraded.

  View details for DOI 10.1016/j.jnutbio.2023.109482

  View details for PubMedID 37839758

• Telomere biology disorders may manifest as common variable immunodeficiency (CVID). Clinical immunology (Orlando, Fla.) Rolles, B., Caballero-Oteyza, A., Proietti, M., Goldacker, S., Warnatz, K., Camacho-Ordonez, N., Prader, S., Schmid, J. P., Vieri, M., Isfort, S., Meyer, R., Kirschner, M., Brümmendorf, T. H., Beier, F., Grimbacher, B. 2023; 257: 109837

  Abstract

  Telomere biology disorders (TBD) are caused by germline pathogenic variants in genes related to telomere maintenance and are characterized by critically short telomeres. In contrast to classical dyskeratosis congenita (DC), which is typically diagnosed in infancy, adult or late onset TBD frequently lack the typical DC triad and rather show variable organ manifestations and a cryptic disease course, thus complicating its diagnosis. Common variable immunodeficiency (CVID), on the other hand, is a primary antibody deficiency (PAD) syndrome. PADs are a heterogenous group of diseases characterized by hypogammaglobulinemia which occurs due to dysfunctional B lymphocytes and additional autoimmune and autoinflammatory complications. Genetic screening reveals a monogenic cause in a subset of CVID patients (15-35%). In our study, we screened the exomes of 491 CVID patients for the occurrence of TBD-related variants in 13 genes encoding for telomere/telomerase-associated proteins, which had previously been linked to the disease. We found 110/491 patients (22%) carrying 91 rare candidate variants in these 13 genes. Following the American College of Medical Genetics and Genomics (ACMG) guidelines, we classified two variants as benign, two as likely benign, 64 as variants of uncertain significance (VUS), four as likely pathogenic, and one heterozygous variant in an autosomal recessive disease gene as pathogenic. We performed telomere length measurement in 42 of the 110 patients with candidate variants and CVID. Two of these 42 patients showed significantly shorter telomeres compared to controls in both lymphocytes and granulocytes. Following the evaluation of the published literature and the patient's manifestations, we re-classified two VUS as likely pathogenic variants. Thus, 0.5-1% of all CVID patients in our study carry possibly pathogenic variants in telomere/telomerase-associated genes. Our data adds CVID to the broad clinical spectrum of cryptic adult-onset TBD. As the molecular diagnosis greatly impacts patient management and treatment strategies, we advise inclusion of all TBD-associated genes-despite their low prevalence-into the molecular screening of patients with antibody deficiencies.

  View details for DOI 10.1016/j.clim.2023.109837

  View details for PubMedID 37944684

• A Simple Prediction Model of Outcomes after Allogeneic Hematopoietic Stem Cell Transplant (HCT) in Myelodysplastic Syndromes Using HCT-Comorbidity Index, Cytogenetic Risk, and Platelet Count Frumm, S. M., Kim, H. T., Kelkar, A. H., Ho, V. T., Gooptu, M., Gibson, C., Koreth, J., Shapiro, R. M., Romee, R., Nikiforow, S., Antin, J. H., Soiffer, R. J., Rolles, B., Shimony, S., Bewersdorf, J., Kewan, T., Alhajahjeh, A., Luskin, M. R., Garcia, J. S., Chen, E. C., Lane, A. A., Wadleigh, M., Winer, E. S., Stone, R. M., DeAngelo, D. J., Zeidan, A. M., Lindsley, C., Cutler, C., Stahl, M. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-185315

  View details for Web of Science ID 001159306708218

• Analysis of the Impact of Body Mass Index (BMI) on the Durability of Response in Patients with Aplastic Anemia Treated with Weight-Adjusted Horse Anti-Thymocyte Globulin (hATG) Walter, J., Rolles, B., Schumacher, Y., Theis, F., Hansmann, L., Heudobler, D., Radsak, M., Heuser, M., Georgi, J., Chromik, J., Drexler, B., Schubert, J., Kricheldorf, K., Isfort, S., Panse, J., Bruemmendorf, T. H., Beier, F. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-183075

  View details for Web of Science ID 001159900802253

• Impact of Type of Hypomethylating Agent (HMA) Used on Outcomes of Patients (Pts) with Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS) - a Large, Multicenter, Retrospective Analysis Bewersdorf, P., Kewan, T., Blaha, O., Stahl, M., Al Ali, N. H., DeZern, A. E., Sekeres, M. A., Uy, G. L., Carraway, H. E., Desai, P., Griffiths, E. A., Stein, E. M., Brunner, A. M., McMahon, C. M., Zeidner, J. F., Savona, M. R., Stempel, J. M., Chandhok, N., Ramaswamy, R., Roboz, G. J., Rolles, B., Wang, E. S., Harris, A. C., Amaya, M. L., Hawkins, H., Grenet, J., Gurnari, C., Shallis, R. M., Xie, Z., Maciejewski, J. P., Sallman, D. A., Della Porta, M., Komrokji, R. S., Zeidan, A. M. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-178728

  View details for Web of Science ID 001159740308102

• Post Allogeneic Stem Cell Transplant Outcomes Following Response to Hypomethylating Agent Therapy in Myelodysplastic Syndromes Are Predicted By Persistent International Prognostic Scoring System-Molecular Risk Frumm, S. M., Kim, H. T., Kelkar, A. H., Ho, V. T., Gooptu, M., Gibson, C., Koreth, J., Shapiro, R. M., Romee, R., Nikiforow, S., Antin, J. H., Soiffer, R. J., Rolles, B., Shimony, S., Bewersdorf, J., Kewan, T., Alhajahjeh, A., Luskin, M. R., Garcia, J. S., Chen, E. C., Lane, A. A., Wadleigh, M., Winer, E. S., Stone, R. M., DeAngelo, D. J., Zeidan, A. M., Lindsley, C., Cutler, C., Stahl, M. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-185220

  View details for Web of Science ID 001159740304229

• Validation of the Molecular International Prognostic Scoring System (IPSS-M) in Patients (Pts) with Myelodysplastic Syndromes/Neoplasms (MDS) Who Were Treated with Hypomethylating Agents (HMA) Kewan, T., Bewersdorf, J., Blaha, O., Stahl, M., Ali, N., DeZern, A. E., Sekeres, M. A., Carraway, H. E., Desai, P., Griffiths, E. A., Stein, E. M., Brunner, A. M., Amaya, M. L., Zeidner, J. F., Savona, M. R., Stempel, J. M., Chandhok, N., Logothetis, C., Ramaswamy, R., Rose, A., Roboz, G. J., Rolles, B., Wang, E. S., Harris, A. C., Shallis, R. M., Xie, Z., Padron, E., Maciejewski, J. P., Sallman, D. A., Della Porta, M., Komrokji, R. S., Zeidan, A. M. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-186340

  View details for Web of Science ID 001159740303103

• Validation of the Molecular International Prognostic Scoring System (IPSS-M) in Patients (Pts) with Myelodysplastic Syndromes/Neoplasms (MDS) Who Underwent Allogenic Stem Cell Transplantation (HSCT) Kewan, T., Bewersdorf, J., Blaha, O., Stahl, M., Al Ali, N. H., DeZern, A. E., Sekeres, M. A., Uy, G. L., Carraway, H. E., Desai, P., Griffiths, E. A., Stein, E. M., Brunner, A. M., Amaya, M. L., Zeidner, J. F., Savona, M. R., Stempel, J. M., Chandhok, N., Logothetis, C., Cochran, H., Rose, A., Roboz, G. J., Wang, E. S., Rolles, B., Harris, A. C., Shallis, R. M., Xie, Z., Padron, E., Maciejewski, J. P., Sallman, D. A., Della Porta, M., Komrokji, R. S., Zeidan, A. M. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-186578

  View details for Web of Science ID 001159900800181

• Validation of the Composite Complete Response (cCR) Definitions in the International Working Group (IWG) 2023 Criteria in Patients (Pts) with Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS) Treated with Hypomethylating Agents (HMA) - a Large, Multicenter, Retrospective Analysis from the Validate Database Bewersdof, J., Kewan, T., Blaha, O., Stahl, M., Al Ali, N. H., DeZern, A. E., Sekeres, M. A., Uy, G. L., Carraway, H. E., Desai, P., Griffiths, E. A., Stein, E. M., Brunner, A. M., McMahon, C. M., Zeidner, J. F., Savona, M. R., Stempel, J. M., Chandhok, N., Logothetis, C., Roboz, G. J., Rolles, B., Wang, E. S., Harris, A. C., Amaya, M. L., Hawkins, H., Grenet, J., Shallis, R. M., Xie, Z., Maciejewski, J. P., Sallman, D. A., Della Porta, M., Komrokji, R. S., Zeidan, A. M. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-180299

  View details for Web of Science ID 001159306701081

• Clinical Implications of TP53 Mutations/Allelic State in Patients (Pts) with Myelodysplastic Syndromes/Neoplasms (MDS) Treated with Hypomethylating Agents (HMA)- a Multicenter, Retrospective Analysis from the Validate Database Kewan, T., Bewersdorf, J., Blaha, O., Stahl, M., Al Ali, N. H., DeZern, A. E., Sekeres, M. A., Carraway, H. E., Desai, P., Griffiths, E. A., Stein, E. M., Brunner, A. M., Amaya, M. L., Zeidner, J. F., Savona, M. R., Stempel, J. M., Chandhok, N., Cochran, H., Ramaswamy, R., Singh, A., Roboz, G. J., Rolles, B., Wang, E. S., Harris, A. C., Shallis, R. M., Xie, Z., Padron, E., Maciejewski, J. P., Della Porta, M., Komrokji, R. S., Sallman, D. A., Zeidan, A. M. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-186875

  View details for Web of Science ID 001159306704026

• TP53 mutations and Their Impact on Survival in Patients with Myeloproliferative Neoplasms Rolles, B., De Oliveira Filho, C., Keating, J., Luskin, M. R., DeAngelo, D. J., Lindsley, C., Kim, A. S., Hem, J., Kim, C. J., Weeks, L. D., Wazir, M., How, J., Marneth, A. E., Liu, Y., Aryee, M. J., Tsai, H. K., Stahl, M., Mullally, A. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-185024

  View details for Web of Science ID 001159740303023

• Evaluation of the Molecular International Prognostic Scoring System (IPSS-M) in Patients (Pts) with Myelodysplastic Syndromes/Neoplasms (MDS) with Missing Molecular Data Kewan, T., Bewersdorf, J., Blaha, O., Stahl, M., Al Ali, N. H., DeZern, A. E., Sekeres, M. A., Carraway, H. E., Desai, P., Griffiths, E. A., Stein, E. M., Brunner, A. M., Amaya, M. L., Zeidner, J. F., Savona, M. R., Stempel, J. M., Chandhok, N., Logothetis, C., Cochran, H., Singh, A., Roboz, G. J., Rolles, B., Wang, E. S., Harris, A. C., Shallis, R. M., Xie, Z., Padron, E., Sallman, D. A., Maciejewski, J. P., Della Porta, M., Komrokji, R. S., Zeidan, A. M. ELSEVIER. 2023

  View details for DOI 10.1182/blood-2023-187053

  View details for Web of Science ID 001159740308096

• Editorial: Zinc in health and disease management. Frontiers in nutrition González-Iglesias, H., Lengyel, I., Rolles, B. 2023; 10: 1242840

  View details for DOI 10.3389/fnut.2023.1242840

  View details for PubMedID 37492591

  View details for PubMedCentralID PMC10364589

• Eltrombopag Preserves the Clonogenic Potential of Hematopoietic Stem Cells During Treatment With Antithymocyte Globulin in Patients With Aplastic Anemia. HemaSphere Vieri, M., Rolles, B., Crocioni, M., Schemionek-Reinders, M., Isfort, S., Panse, J., Brümmendorf, T. H., Beier, F. 2023; 7 (6): e906

  Abstract

  Aplastic anemia (AA) is frequently caused by a T-cell mediated autoimmune depletion of the hematopoietic stem and progenitor cell (HSPC) compartment. Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine represents the first-line treatment of AA. One side effect of ATG therapy is the release of proinflammatory cytokines such as interferon-gamma (IFN-γ), which is considered a major factor in the pathogenic autoimmune depletion of HSPC. Recently, eltrombopag (EPAG) was introduced for therapy of refractory AA patients due to its ability to bypass IFN-γ-mediated HSPC inhibition among other mechanisms. Clinical trials have evidenced that EPAG started simultaneously with IST leads to a higher response rate compared with its later administration schedules. We hypothesize that EPAG might protect HSPC from negative effects of ATG-induced release of cytokines. We observed a significant decrease in colony numbers when both healthy peripheral blood (PB) CD34+ cells and AA-derived bone marrow cells were cultured in the presence of serum from patients under ATG treatment, as compared with before treatment. Consistent with our hypothesis, this effect could be rescued by adding EPAG in vitro to both healthy and AA-derived cells. By employing an IFN-γ neutralizing antibody, we also demonstrated that the deleterious early ATG effects on the healthy PB CD34+ compartment were mediated at least partially by IFN-γ. Hence, we provide evidence for the hitherto unexplained clinical observation that concomitant use of EPAG in addition to IST comprising ATG leads to improved response in patients with AA.

  View details for DOI 10.1097/HS9.0000000000000906

  View details for PubMedID 37304936

  View details for PubMedCentralID PMC10249716

• DDX41 germline variants causing donor cell leukemia indicate a need for further genetic workup in the context of hematopoietic stem cell transplantation. Blood cancer journal Rolles, B., Meyer, R., Begemann, M., Elbracht, M., Jost, E., Stelljes, M., Kurth, I., Brümmendorf, T. H., Silling, G. 2023; 13 (1): 73

  View details for DOI 10.1038/s41408-023-00846-2

  View details for PubMedID 37160870

  View details for PubMedCentralID PMC10170132

• CALR-mutated cells are vulnerable to combined inhibition of the proteasome and the endoplasmic reticulum stress response. Leukemia Jutzi, J. S., Marneth, A. E., Jiménez-Santos, M. J., Hem, J., Guerra-Moreno, A., Rolles, B., Bhatt, S., Myers, S. A., Carr, S. A., Hong, Y., Pozdnyakova, O., van Galen, P., Al-Shahrour, F., Nam, A. S., Mullally, A. 2023; 37 (2): 359-369

  Abstract

  Cancer is driven by somatic mutations that provide a fitness advantage. While targeted therapies often focus on the mutated gene or its direct downstream effectors, imbalances brought on by cell-state alterations may also confer unique vulnerabilities. In myeloproliferative neoplasms (MPN), somatic mutations in the calreticulin (CALR) gene are disease-initiating through aberrant binding of mutant CALR to the thrombopoietin receptor MPL and ligand-independent activation of JAK-STAT signaling. Despite these mechanistic insights into the pathogenesis of CALR-mutant MPN, there are currently no mutant CALR-selective therapies available. Here, we identified differential upregulation of unfolded proteins, the proteasome and the ER stress response in CALR-mutant hematopoietic stem cells (HSCs) and megakaryocyte progenitors. We further found that combined pharmacological inhibition of the proteasome and IRE1-XBP1 axis of the ER stress response preferentially targets Calr-mutated HSCs and megakaryocytic-lineage cells over wild-type cells in vivo, resulting in an amelioration of the MPN phenotype. In serial transplantation assays following combined proteasome/IRE1 inhibition for six weeks, we did not find preferential depletion of Calr-mutant long-term HSCs. Together, these findings leverage altered proteostasis in Calr-mutant MPN to identify combinatorial dependencies that may be targeted for therapeutic benefit and suggest that eradicating disease-propagating Calr-mutant LT-HSCs may require more sustained treatment.

  View details for DOI 10.1038/s41375-022-01781-0

  View details for PubMedID 36473980

• Telomere length dynamics measured by flow-FISH in patients with obesity undergoing bariatric surgery. Scientific reports Rolles, B., Ferreira, M. S., Vieri, M., Rheinwalt, K. P., Schmitz, S. M., Alizai, P. H., Neumann, U., Brümmendorf, T. H., Beier, F., Ulmer, T. F., Tometten, M. 2023; 13 (1): 304

  Abstract

  Obesity has negative effects on comorbidities, health-related quality of life and survival. Telomere length (TL) changes after bariatric surgery have been reported, but the studies are contradictory, and analyses using state-of-the art techniques for TL measurement, such as flow-FISH, are sparse. We measured TL dynamics via flow-FISH in patients undergoing bariatric surgery and compared their TL with 105 healthy individuals. Patients with obesity who underwent bariatric surgery were included. Lymphocyte and granulocyte absolute and age-adjusted (aa) TL were analyzed by flow-FISH before (preoperative cohort, n = 45) and after surgery (follow-up cohort, n = 35) at month 5.5 ± 3.9 (mean ± standard deviation [SD]). The initial lymphocyte aaTL was significantly shorter (-0.37 kb ± 0.18 kb, P = 0.045) in patients with obesity, while the granulocyte aaTL was not different from that in the healthy comparison population (0.28 kb ± 0.17 kb, P = 0.11). The telomere dynamics after surgery showed an increase in mean TL in both lymphocytes and granulocytes of patients with a pronounced BMI loss of ≥ 10 kg/m2. We did not find any association between TL increase after surgery and age, sex or the type of procedure selected for bariatric surgery. We confirmed that patients suffering from obesity have significantly shorter lymphocyte TL using flow-FISH. Along with and dependent on the degree of weight reduction after bariatric surgery, TL significantly increased in both lymphocytes and granulocytes after a mean of 5.5 months. Our results show that bariatric surgery affects not only body weight but also biomarkers of aging, such as TL.

  View details for DOI 10.1038/s41598-022-27196-6

  View details for PubMedID 36609582

  View details for PubMedCentralID PMC9818052

• Molecular Pathogenesis of Myeloproliferative Neoplasms. Current hematologic malignancy reports Rolles, B., Mullally, A. 2022; 17 (6): 319-329

  Abstract

  Myeloproliferative neoplasms (MPNs) are chronic hematological malignancies characterized by increased proliferation of MPN stem and myeloid progenitor cells with or without bone marrow fibrosis that typically lead to increased peripheral blood cell counts. The genetic and cytogenetic alterations that initiate and drive the development of MPNs have largely been defined, and we summarize these here.In recent years, advances in understanding the pathogenesis of MPNs have defined a long-preclinical phase in JAK2-mutant MPN, identified genetic loci associated with MPN predisposition and uncovered mechanistic insights in CALR-mutant MPN. The integration of molecular genetics into prognostic risk models is well-established in myelofibrosis and ongoing studies are interrogating the prognostic implications of concomitant mutations in ET and PV. Despite all these advances, the field is deficient in clonally selective therapies to effectively target the MPN clone at any stage of disease, from pre-clinical to advanced. Although the biological understanding of the pathogenesis of MPNs has progressed quickly, substantial knowledge gaps remain, including in the molecular mechanisms underlying MPN progression and myelofibrotic transformation. An ongoing goal for the MPN field is to translate advances in biological understanding to improved treatments for patients.

  View details for DOI 10.1007/s11899-022-00685-1

  View details for PubMedID 36336766

  View details for PubMedCentralID 2909585

• Impaired Overall Survival in Young Patients With Acute Myeloid Leukemia and Variants in Genes Predisposing for Myeloid Malignancies. HemaSphere Kirschner, M., Rolles, B., Crysandt, M., Röllig, C., Stölzel, F., Kramer, M., Bornhäuser, M., Serve, H., Platzbecker, U., Müller-Tidow, C., Kricheldorf, K., Vieri, M., Begemann, M., Maurer, A., Wlodarski, M. W., Sahoo, S. S., Brümmendorf, T. H., Jost, E., Beier, F. 2022; 6 (11): e787

  View details for DOI 10.1097/HS9.0000000000000787

  View details for PubMedID 36258922

  View details for PubMedCentralID PMC9561384

• Towards personalized medicine with iPS cell technology: a case report of advanced systemic mastocytosis with associated eosinophilia. Annals of hematology Atakhanov, S., Christen, D., Rolles, B., Schüler, H. M., Panse, J., Chatain, N., Koschmieder, S., Brümmendorf, T. H., Toledo, M. A., Zenke, M. 2022; 101 (11): 2533-2536

  View details for DOI 10.1007/s00277-022-04975-9

  View details for PubMedID 36125543

  View details for PubMedCentralID PMC9486762

• Effective treatment of advanced Hodgkin lymphoma with a modified BEACOPP regimen for a patient with demyelinating hereditary motor and sensory neuropathy type 1 (HMSN1). Clinical case reports Hess, P. P., Ventura Ferreira, M. S., Rolles, B., Kirschner, M., Holtbernd, F., Tometten, M., Brümmendorf, T. H., Beier, F. 2022; 10 (5): e05766

  Abstract

  Treatment for Hodgkin lymphoma (HL) in adults comprises substantial risk of chemotherapy-induced peripheral neurotoxicity. Here, we describe the case of patient with Charcot-Marie-Tooth disease or HSMN1 and advanced Hodgkin lymphoma undergoing treatment with modified BEACOPP achieving complete remission without major aggravation of neurological symptoms.

  View details for DOI 10.1002/ccr3.5766

  View details for PubMedID 35540715

  View details for PubMedCentralID PMC9069391

• Retrospective observational study evaluating zinc plasma level in patients undergoing thoracoabdominal aortic aneurysm repair and its correlation with outcome. Scientific reports Rolles, B., Wessels, I., Doukas, P., Kotelis, D., Rink, L., Vieri, M., Beier, F., Jacobs, M., Gombert, A. 2021; 11 (1): 24348

  Abstract

  Thoracoabdominal aortic aneurysm (TAAA) repair is related to a relevant morbidity and in-hospital mortality rate. In this retrospective observational single-center study including serum zinc levels of 33 patients we investigated the relationship between zinc and patients' outcome following TAAA repair. Six patients died during the hospital stay (18%). These patients showed significantly decreased zinc levels before the intervention (zinc levels before intervention: 60.09 µg/dl [survivors] vs. 45.92 µg/dl [non-survivors]). The post-interventional intensive care SOFA-score (Sepsis-related organ failure assessment) (at day 2) as well as the SAPS (Simplified Acute Physiology Score) (at day 2) showed higher score points in case of low pre-interventional zinc levels. No significant correlation between patient comorbidities and zinc level before intervention, except for peripheral arterial disease (PAD), which was significantly correlated to reduced baseline zinc levels, was observed. Septic shock, pneumonia and urinary tract infections were not associated to reduced zinc levels preoperatively as well as during therapy. Patients with adverse outcome after TAAA repair showed reduced pre-interventional zinc levels. We speculate that decreased zinc levels before intervention may be related to a poorer outcome because of poorer physical status as well as negatively altered perioperative inflammatory response.

  View details for DOI 10.1038/s41598-021-03877-6

  View details for PubMedID 34934131

  View details for PubMedCentralID PMC8692510

• Intracellular zinc during cell activation and zinc deficiency. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) Rolles, B., Maywald, M., Rink, L. 2021; 68: 126864

  Abstract

  Zinc is an essential trace element having manifold functions within living cells. Zinc deficiency but also zinc excess impairs cell-specific functions whereas a balanced zinc level is required for an adequate cell behavior.This study deals with the impact of cellular priming due to stimulation with interleukin (IL)-1, IL-2, IL-4, IL-6 or the chemokine CXCL12a and its subsequent influence on the intracellular free zinc concentration. Since cellular priming and activation is essential for proper immunological reactions, and across that highly cell-type specific, we investigated T cells, B cells, and peripheral blood mononuclear cells (PBMCs). Additionally, alterations of the intracellular zinc content was investigated by inducing zinc deficiency using the zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethane-1,2-diamine (TPEN) with subsequent re-supplementation of zinc, hence generating an intracellular zinc flux. Evaluation of zinc staining with FluoZin3-AM, Zinpyr-1 and Zinquin was done by flow cytometry or by fluorescence microscopy.Our results indicate that cellular priming for different periods of time (10 minutes/one hour) causes decreased intracellular free zinc concentrations in the FluoZin3-AM staining and increased zinc concentrations stained with Zinpyr-1. Furthermore, zinc supplementation after induced zinc deficiency leads to a fast and excessive rise of the intracellular free zinc levels in most cellular compartments.Our study emphasizes the importance of zinc homeostasis and zinc distribution during cellular priming and for certain signaling cascades especially in T and B cells. Moreover, we demonstrated that zinc re-supplementation of zinc deficient cells results in significantly elevated intracellular free zinc concentrations compared to untreated controls. Hence, this underlines the need of a balanced zinc homeostasis for proper immune cell function.

  View details for DOI 10.1016/j.jtemb.2021.126864

  View details for PubMedID 34562730

• Telomere Shortening in Peripheral Leukocytes Is Associated With Poor Survival in Cancer Patients Treated With Immune Checkpoint Inhibitor Therapy. Frontiers in oncology Rolles, B., Gorgulho, J., Tometten, M., Roderburg, C., Vieri, M., Abels, A., Vucur, M., Heymann, F., Tacke, F., Brümmendorf, T. H., Luedde, T., Beier, F., Loosen, S. H. 2021; 11: 729207

  Abstract

  Immune checkpoint inhibitor (ICI) therapy represents a new standard of care for an increasing number of malignancies. Nevertheless, response rates and outcome of ICI treatment vary between individuals and the identification of predictive markers or hints towards immune cell exhaustion during therapy has remained a major challenge. Leukocyte telomere length is an established predictive biomarker of replicative aging and cellular proliferative potential in various hematological diseases. However, its relevance in the context of ICI therapy has not been investigated to date. Here, we analyze the age-adapted delta telomere length (ΔTL) of peripheral leukocytes as a potential predictive and prognostic marker in patients undergoing ICI therapy.Age-adapted delta telomere length (ΔTL) of 84 patients treated with ICIs for solid malignancies was measured via quantitative real-time PCR. ΔTL was correlated with outcome and clinical data.ΔTL was not significantly altered between patients with different tumor entities or tumor stages and did not predict tumor response to ICI therapy. However, ΔTLs at initiation of treatment were a prognostic marker for overall survival (OS). When using a calculated ideal cut-off value, the median OS in patients with shorter ΔTL was 5.7 months compared to 18.0 months in patients showing longer ΔTL. The prognostic role of age-adapted ΔTL was further confirmed by uni- and multivariate Cox-regression analyses.In the present study, we demonstrate that shorter telomere lengths in peripheral blood leukocytes are associated with a significantly impaired outcome in patients receiving ICI therapy across different malignancies. We explain our findings by hypothesizing an older replicative age in peripheral leukocytes of patients with an impaired overall survival, reflected by a premature TL shortening. Whether this association is ICI-specific remains unknown. Further follow-up studies are needed to provide insights about the exact mechanism of how shortened telomeres eventually affect OS and could help guiding therapeutic decisions in future.

  View details for DOI 10.3389/fonc.2021.729207

  View details for PubMedID 34490122

  View details for PubMedCentralID PMC8417059

• Androgen derivatives improve blood counts and elongate telomere length in adult cryptic dyskeratosis congenita. British journal of haematology Kirschner, M., Vieri, M., Kricheldorf, K., Ferreira, M. S., Wlodarski, M. W., Schwarz, M., Balabanov, S., Rolles, B., Isfort, S., Koschmieder, S., Höchsmann, B., Panse, J., Brümmendorf, T. H., Beier, F. 2021; 193 (3): 669-673

  Abstract

  Dyskeratosis Congenita (DKC) is a systemic disorder caused by mutations resulting in impaired telomere maintenance. Clinical features include bone marrow failure and an increased risk of developing hematological malignancies. There are conflicting data whether androgen derivatives (AD) can elongate telomeres in vivo and whether AD treatment enhances the risk of gaining myelodysplastic syndrome-related mutations. Seven TERC or TERT-mutated DKC patients underwent AD treatment. All patients revealed hematological response. Telomere length of lymphocytes and granulocytes increased significantly and no MDS-related mutations were detected. Pending longer follow-up, treatment with AD seems to represent an efficient and safe therapy for DKC patients.

  View details for DOI 10.1111/bjh.16997

  View details for PubMedID 32744739

• Phosphatidylserine Supplementation as a Novel Strategy for Reducing Myocardial Infarct Size and Preventing Adverse Left Ventricular Remodeling. International journal of molecular sciences Schumacher, D., Curaj, A., Staudt, M., Cordes, F., Dumitraşcu, A. R., Rolles, B., Beckers, C., Soppert, J., Rusu, M., Simsekyilmaz, S., Kneizeh, K., Ramachandra, C. J., Hausenloy, D. J., Liehn, E. A. 2021; 22 (9)

  Abstract

  Phosphatidylserines are known to sustain skeletal muscle activity during intense activity or hypoxic conditions, as well as preserve neurocognitive function in older patients. Our previous studies pointed out a potential cardioprotective role of phosphatidylserine in heart ischemia. Therefore, we investigated the effects of phosphatidylserine oral supplementation in a mouse model of acute myocardial infarction (AMI). We found out that phosphatidylserine increases, significantly, the cardiomyocyte survival by 50% in an acute model of myocardial ischemia-reperfusion. Similar, phosphatidylserine reduced significantly the infarcted size by 30% and improved heart function by 25% in a chronic model of AMI. The main responsible mechanism seems to be up-regulation of protein kinase C epsilon (PKC-ε), the main player of cardio-protection during pre-conditioning. Interestingly, if the phosphatidylserine supplementation is started before induction of AMI, but not after, it selectively inhibits neutrophil's activation, such as Interleukin 1 beta (IL-1β) expression, without affecting the healing and fibrosis. Thus, phosphatidylserine supplementation may represent a simple way to activate a pre-conditioning mechanism and may be a promising novel strategy to reduce infarct size following AMI and to prevent myocardial injury during myocardial infarction or cardiac surgery. Due to the minimal adverse effects, further investigation in large animals or in human are soon possible to establish the exact role of phosphatidylserine in cardiac diseases.

  View details for DOI 10.3390/ijms22094401

  View details for PubMedID 33922385

  View details for PubMedCentralID PMC8122843

• Prevalence of Inherited Predisposition Syndromes in Young Patients with Acute Myeloid Leukemia and Aberrant Karyotype Kirschner, M., Rolles, B., Crysandt, M., Rollig, C., Stolzel, F., Bornhauser, M., Muller-Tidow, C., Kricheldorf, K., Vieri, M., Begemann, M., Maurer, A., Panse, J., Isfort, S., Wlodarski, M., Sahoo, S., Brummendorf, T. H., Jost, E., Beier, F. AMER SOC HEMATOLOGY. 2020

  View details for DOI 10.1182/blood-2020-142815

  View details for Web of Science ID 000607205604171

• Comparable Effects of the Androgen Derivatives Danazol, Oxymetholone and Nandrolone on Telomerase Activity in Human Primary Hematopoietic Cells from Patients with Dyskeratosis Congenita. International journal of molecular sciences Vieri, M., Kirschner, M., Tometten, M., Abels, A., Rolles, B., Isfort, S., Panse, J., Brümmendorf, T. H., Beier, F. 2020; 21 (19)

  Abstract

  Dyskeratosis congenita (DKC) is a rare inherited disease of impaired telomere maintenance that progressively leads to multi-organ failure, including the bone marrow. By enhancing telomerase activity, androgen derivatives (ADs) are a potential therapeutic option able to re-elongate previously shortened telomeres. Danazol, oxymetholone, and nandrolone are ADs most frequently used to treat DKC. However, no direct in vitro analyses comparing the efficacy of these ADs have been conducted so far. We therefore treated mononuclear cells derived from peripheral blood and bone marrow of four patients with mutations in telomerase reverse transcriptase (TERT, n = 1),in the telomerase RNA component (TERC, n = 2) and in dyskerin pseudouridine synthase 1 (DKC1, n = 1) and found no substantial differences in the activity of these three agents in patients with TERC/TERT mutations. All AD studied produced comparable improvements of proliferation rates as well as degrees of telomere elongation. Increased TERT expression levels were shown with danazol and oxymetholone. The beneficial effects of all ADs on proliferation of bone marrow progenitors could be reversed by tamoxifen, an estrogen antagonist abolishing estrogen receptor-mediated TERT expression, thereby underscoring the involvement of TERT in AD mechanism of action. In conclusion, no significant differences in the ability to functionally enhance telomerase activity could be observed for the three AD studied in vitro. Physicians therefore might choose treatment based on patients' individual co-morbidities, e.g., pre-existing liver disease and expected side-effects.

  View details for DOI 10.3390/ijms21197196

  View details for PubMedID 33003434

  View details for PubMedCentralID PMC7584039

• The Potential Impact of Zinc Supplementation on COVID-19 Pathogenesis. Frontiers in immunology Wessels, I., Rolles, B., Rink, L. 2020; 11: 1712

  Abstract

  During the current corona pandemic, new therapeutic options against this viral disease are urgently desired. Due to the rapid spread and immense number of affected individuals worldwide, cost-effective, globally available, and safe options with minimal side effects and simple application are extremely warranted. This review will therefore discuss the potential of zinc as preventive and therapeutic agent alone or in combination with other strategies, as zinc meets all the above described criteria. While a variety of data on the association of the individual zinc status with viral and respiratory tract infections are available, study evidence regarding COVID-19 is so far missing but can be assumed as was indicated by others and is detailed in this perspective, focusing on re-balancing of the immune response by zinc supplementation. Especially, the role of zinc in viral-induced vascular complications has barely been discussed, so far. Interestingly, most of the risk groups described for COVID-19 are at the same time groups that were associated with zinc deficiency. As zinc is essential to preserve natural tissue barriers such as the respiratory epithelium, preventing pathogen entry, for a balanced function of the immune system and the redox system, zinc deficiency can probably be added to the factors predisposing individuals to infection and detrimental progression of COVID-19. Finally, due to its direct antiviral properties, it can be assumed that zinc administration is beneficial for most of the population, especially those with suboptimal zinc status.

  View details for DOI 10.3389/fimmu.2020.01712

  View details for PubMedID 32754164

  View details for PubMedCentralID PMC7365891

• Common Variable Immunodeficiency (CVID) in Adults As First Manifestation of (cryptic) Dyskeratosis Congenita Rolles, B., Bulashevska, A., Proietti, M., Goldacker, S., Warnatz, K., Camacho-Ordonez, N., Vieri, M., Kirschner, M., Brummendorf, T. H., Grimbacher, B., Beier, F. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-128915

  View details for Web of Science ID 000577160401033

• Influence of zinc deficiency and supplementation on NK cell cytotoxicity JOURNAL OF FUNCTIONAL FOODS Rolles, B., Maywald, M., Rink, L. 2018; 48: 322-328

  View details for DOI 10.1016/j.jff.2018.07.027

  View details for Web of Science ID 000447573600035