Towards a New Approach to Treating Chronic Blood Disorders

Researchers at Karl Landsteiner University identified an immune mechanism that points towards targeted therapies for certain blood neoplasms. Blocking a specific molecular signal on immune cells may restore the ability to fight mutated cells.

Krems, Austria, 5 November 2026 – A previously unrecognised weakness in the immune defences against certain blood neoplasms could offer a promising target for future treatments. Researchers have discovered that natural killer cells, which normally help the body eliminate malignant cells, remain remarkably active in patients with a particular genetic form of blood neoplasms. However, their ability to fight the disease appears to be restricted by an inhibitory molecular signal. Blocking this signal restored immune activity against diseased cells in laboratory experiments and showed encouraging effects in an experimental disease model. The findings, obtained by an international research team led by Karl Landsteiner University (klu Krems), suggest a new approach to treating patients with specific forms of chronic blood disorders. They could also help identify those most likely to benefit from future immunotherapy.

Myeloproliferative neoplasms (MPNs) are chronic blood disorders characterised by excessive blood cell production. Depending on the subtype, patients may develop dangerous blood clots, bone marrow scarring or even progress to acute myeloid leukaemia. Existing treatments can control symptoms and complications but rarely eliminate the disease. Genetic mutations differ between MPN patients and may affect treatment responses. One such mutation affects a protein called calreticulin (CALR). Although immune function is known to be impaired in MPNs, little was understood about how this mutation affects the body’s natural defences. Researchers from the Department of Pharmacology at klu Krems therefore investigated whether these differences could offer opportunities for more selective treatments.

Active but Restrained

“Natural killer cells are among the body’s first lines of defence against cancer,” explains Prof. Dr. Dagmar Stoiber-Sakaguchi, Head of the Department of Pharmacology at klu Krems, who led the study. “What makes our findings particularly interesting is that these cells retain much of their ability to attack malignant cells in patients with CALR mutations. The problem appears to be that their activity is being held back.”

The researchers compared natural killer cells from patients carrying CALR mutations with those from patients harbouring mutations in another frequently affected gene, JAK2. They found striking differences. While natural killer cells from JAK2-mutant patients showed signs of impaired function, those from CALR-mutant patients retained their ability to release substances involved in killing abnormal cells. However, these cells also displayed unusually high levels of TIGIT, a receptor that can suppress immune responses. This suggests that their considerable anti-cancer potential may be held back by an inhibitory signal.

Further investigations revealed a possible explanation. Blood-forming precursor cells from affected patients displayed increased levels of CD112, a molecule capable of activating the inhibitory TIGIT receptor. In addition, the researchers identified elevated concentrations of several immune-modulating proteins in the patients’ blood. Together, these findings suggest that the disease creates conditions that stimulate natural killer cells while simultaneously restricting their ability to attack malignant targets.

Releasing the Brakes

The potential therapeutic relevance became apparent when the team blocked TIGIT using a specific antibody. In laboratory experiments, natural killer cells became more effective at destroying abnormal cells. In an in vivo model of CALR-mutant disease, antibody treatment also showed a tendency to reduce the elevated blood platelet counts characteristic of this form of MPN.

“These results provide a rationale for investigating TIGIT blockade as an additional treatment option for patients with CALR-mutant disease,” say the study’s two co-first authors, Ass.-Prof. Dr. Agnieszka Witalisz-Siepracka and Theresa Harm, MSc. “Rather than attacking mutated cells directly, such a therapy could help the patient’s own immune system control them more effectively.”

The findings remain preclinical and require confirmation in larger patient groups and further experimental studies. Nevertheless, antibodies targeting TIGIT are already being investigated clinically in other cancer settings, potentially facilitating future research into their use against MPNs. The results also raise the possibility of combining TIGIT blockade with other immunotherapeutic approaches.

Conducted with scientific and clinical collaborators from Austria, Germany and the United Kingdom, the study illustrates the value of combining molecular research with patient-derived material and experimental disease models. At klu Krems, such cooperation forms an important part of research investigating the molecular mechanisms of cancer and their potential translation into more individualised treatment strategies.

Image available on request.

Original publication:
Mutant calreticulin-driven myeloproliferative neoplasms favour the emergence of TIGIT-positive NK cells. A. Witalisz-Siepracka, T. Harm, T. Klampfl, B. Zdársky, B. Ringhofer, E. Gamper, S. Edtmayer, U. Graichen, P. Pavić, S. Geiselhart, J. Foßelteder, G. Hoermann, J. Li, A. R. Green, C. Crodel, J. Wolff, F. H. Heidel, S. Klee, K. Podar, A. Reinisch, A. Zebisch, K. Kollmann, D. Stoiber. Leukemia; https://doi.org/10.1038/s41375-026-03175-y

Karl Landsteiner University (11/2026)

The Karl Landsteiner University (klu Krems) is an internationally recognized educational and research institution on the Campus Krems. The klu Krems offers modern, demand-oriented education and continuing education in medicine and psychology as well as PhD programmes in the fields of mental health and neuroscience, and Tumour Biology. The flexible educational programme is tailored to the needs of students, the requirements of the labour market and the challenges of science. With its university hospitals in Krems, St. Pölten and Tulln, as well as the MedAustron Ion Therapy and Research Centre in Wiener Neustadt, the university provides clinical teaching and research of an international standard. In its research, klu Krems focuses on interdisciplinary areas of high social and health policy relevance, including mental health, neuroscience, oncology, and issues relating to water quality and its impact on health. The university was founded in 2012 and accredited in 2013 by the Agency for Quality Assurance and Accreditation Austria (AQ Austria). Its founding institutions include the Medical University of Vienna, the Vienna University of Technology and the Province of Lower Austria. https://www.kl.ac.at/en

Scientific Contact

Prof. Dr. Dagmar Stoiber-Sakaguchi

Department of Pharmacology

Karl Landsteiner University

Dr.-Karl-Dorrek-Straße 30

3500 Krems / Austria

T +43 2732 72090 470

E dagmar.stoiber@kl.ac.at

W http://www.kl.ac.at

Karl Landsteiner University

Mag. Selma Vrazalica, BA

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