Kaan Boztug Group

Immune Deficiency, Cancer Predisposition & Precision Oncology

Kaan Boztug Email: kaan.boztug(at)ccri.at

Scientific Director, St. Anna Children’s Cancer Research Institute (CCRI) / St. Anna Kinderkrebsforschung
Consultant Pediatric Hematology and Oncology and Head of Pediatric Immunology, St. Anna Children's Hospital
Director, Ludwig Boltzmann Institute and CeRUD Vienna Center for Rare and Undiagnosed Diseases
Associate Professor of Pediatrics, Department of Pediatrics, Medical University of Vienna
Adjunct Principal Investigator, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Head, Jeffrey Modell Foundation Diagnostic and Research Center for Immunodeficiencies Vienna

Team

Research Focus

Our group works at the interface of inborn immune disorders and inherited predisposition to childhood tumors, aiming to understand fundamental mechanisms of immune surveillance relevant to pediatric oncology and immunotherapy approaches. In close collaboration with several other groups at the institute and the St. Anna Children’s Hospital next door, we aim to translate the molecular understanding of childhood cancer (predisposition) to specific pathway modulations for the identification of targeted treatment approaches for pediatric cancer patients.

Introduction

Dysregulation of the immune system can lead to an increased susceptibility to infections, autoimmune manifestations and cancer. While research on immunodeficiencies has so far been primarily focused on the susceptibility to pathogens, the fact that a dysregulated immune system can also lead to malignancy has been largely neglected until recently. We study patients suffering from inherited defects of the immune systems, so-called inborn errors of immunity (IEI), formerly known as primary immunodeficiencies, as (mono)genetic diseases provide unique opportunities to unravel genotype to phenotype relationships and to elucidate the pathogenic mechanisms of immune system disorders and their interaction with malignancy.

Aim

We want to uncover the molecular processes underlying IEIs in order to decipher the highly complex signaling pathways of the human body that are relevant for immunodeficiencies and cancer susceptibility. The investigations of these fundamental mechanisms have an enormous impact on how we understand the development of malignancies. We study the interplay of genes and pathways that play a role in malignant and immune system disorders to enhance our molecular understanding of these diseases.

Approach

We utilize state-of-the art genomic approaches including exome sequencing of patient samples to identify causative genetic mutations, combined with a variety of functional assays to:

Gain a systematic understanding of the molecular basis of human immune (dys)regulation including autoimmunity and childhood cancer predisposition
Elucidate genetics and molecular pathophysiology of rare inborn errors of immunity and to decipher molecular targets for the development of personalized treatment options for immune deficiencies
Identify molecular targets through an institute-wide pediatric precision oncology program for tailored treatment of childhood cancer which may be resistant to standard therapeutic protocols

The provision of highly specialised treatment and care for patients with rare diseases and complex clinical manifestations such as childhood cancer is still a challenge. Our investigations aim to improve our understanding of the molecular architecture of the immune system and its linkage with malignancy with the ultimate goal to improve the wellbeing of patients by developing targeted therapies and personalized medicine approaches.

Kaan Boztug is Director of the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD). The research focus of the LBI-RUD is on rare diseases of the immune system, hematopoiesis, dermatology and the nervous system, which all together account for more than half of all rare diseases. Other focus areas include rare diseases in the field of gastroenterology, hepatology and cancer. CCRI has been a partner institution of LBI-RUD since its conception and launch in 2016.

Selected Articles:

Somekh I*, Thian M*, Medgyesi D, Gülez N, Magg T, Gallón Duque A, Stauber T, Lev A, Genel F, Unal E, Simon AJ, Lee YN, Kalinichenko A, Dmytrus J, Kraakman M, Schiby G, Rohlfs M, Jacobson JM, Özer E, Akcal Ö, Conca R, Patiroglu T, Karakukcu M, Ozcan A, Shahin T, Appella E, Tatematsu M, Martinez-Jaramillo C, Chinn IK, Orange JS, Trujillo-Vargas CM, Franco JL, Hauck F, Somech R§, Klein C§, Boztug K§. CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis. Blood. 2019 Sep 9. pii: blood.2019000644. doi: 10.1182/blood.2019000644. (*shared first authorship, § shared senior and corresponding authorship)
Domínguez Conde C*, Petronczki ÖY*, Baris S*, Willmann KL*, Girardi E, Salzer E, Weitzer S, Ardy RC, Krolo A, Ijspeert H, Kiykim A, Karakoc-Aydiner E, Förster-Waldl E, Kager L, Pickl WF, Superti-Furga G, Martínez J, Loizou J, Ozen A, van der Burg M, Boztug K. Polymerase δ deficiency causes syndromic immunodeficiency with replicative stress. J Clin Invest. 2019 Aug 26. pii: 128903. doi: 10.1172/JCI128903. (* shared first authorship)
Serwas NK*, Hoeger B*, Ardy RC, Stulz SV, Sui Z, Memaran N, Meeths M, Krolo A, Petronczki ÖY, Pfajfer L, Hou TZ, Halliday N, Santos-Valente E, Kalinichenko A, Kennedy A, Mace EM, Mukherjee M, Tesi B, Schrempf A, Pickl WF, Loizou JI, Kain R, Bidmon-Fliegenschnee B, Schickel JN, Glauzy S, Huemer J, Garncarz W, Salzer E, Pierides I, Bilic I, Thiel J, Priftakis P, Banerjee PP, Förster-Waldl E, Medgyesi D, Huber WD, Orange JS, Meffre E, Sansom DM, Bryceson YT, Altman A, Boztug K. Human DEF6 deficiency underlies a novel immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis. Nat Commun. 2019 Jul 15; 10(1):3106. doi: 10.1038/s41467-019-10812-x. (* shared first authorship)
Ozen A*, Comrie WA*, Ardy RC*, Domínguez Conde C, Dalgic B, Beser ÖF, Morawski AR, Karakoc-Aydiner E, Tutar E, Baris S, Ozcay F, Serwas NK, Zhang Y, Matthews HF, Pittaluga S, Folio LR, Unlusoy Aksu A, McElwee JJ, Krolo A, Kiykim A, Baris Z, Gulsan M, Ogulur I, Snapper SB, Houwen RHJ, Leavis HL, Ertem D, Kain R, Sari S, Erkan T, Su HC, Boztug K§, Lenardo MJ§. CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med. 2017 Jul 6; 377(1):52-61. doi: 10.1056/NEJMoa1615887. (* shared first authorship; § shared senior and corresponding authorship)
Salzer E, Cagdas D#, Hons M#, Mace EM#, Garncarz W, Petronczki ÖY, Platzer R, Pfajfer L, Bilic I, Ban SA, Willmann KL, Mukherjee M, Supper V, Hsu HT, Banerjee PP, Sinha P, McClanahan F, Zlabinger GJ, Pickl WF, Gribben JG, Stockinger H, Bennett KL, Huppa JB, Dupré L, Sanal Ö, Jäger U, Sixt M#, Tezcan I#, Orange JS#, Boztug K. RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics. Nat Immunol. 2016 Dec; 17(12):1352-1360. doi: 10.1038/ni.3575. (# equal contribution)