Understanding the oncogenic roles of JAK-STAT signaling and STAT5B in T cell and myeloid malignancies

Led by Heidi Neubauer, PhD

Our focused research team is interested in understanding the role of the JAK-STAT core cancer pathway in two main disease entities, mature T cell leukemias/lymphomas (MaTCLs) and myeloproliferative neoplasms (MPNs). Specifically, our work focuses on studying the role of the oncogenic transcription factor, STAT5B, and modeling aggressive gain-of-function driver mutations in cells and mice in order to explore new therapeutic targeting options and identify novel disease biomarkers.

Developing models and tools for studying rare MaTCLs

Mature T cell leukemias/lymphomas (MaTCLs) are a group of rare hematological malignancies of mostly incurable prospects due to limited efficient therapies and a lack of faithful pre-clinical models. It is increasingly evident that hyperactivation of the JAK-STAT signaling pathway plays a role in these MaTCL diseases. Notably, a hotspot gain-of-function mutation in STAT5B, N642H, has been found in over 120 patients with T cell cancer, and is associated with more aggressive disease, therapy resistance and worse prognosis.

Diagram showing the number (each dot) and blood cancer subtype of patients found with the aggressive gain-of-function STAT5BN642H mutation. Associated publication in Nature Communications.

We are exploiting this oncogenic driver to develop novel pre-clinical models and tools for identifying and testing new therapeutic strategies for these incurable T cell diseases. As we have an interest in translational research, we are generating new mouse models that more closely recapitulate the human disease setting in MaTCL patients, particularly the most aggressive subtypes where currently no pre-clinical models exist. We are also developing novel MaTCL cell lines which we are using as valuable tools to identify oncogenic pathways driven by hyperactive STAT5B, as well as to perform unbiased drug screens to discover small molecule inhibitors that are cytotoxic to these malignant T cells. Ultimately, from both our mechanistic studies employing next generation sequencing technologies, as well as drug-screening efforts, we aim to define new targetable nodes in T cell cancer and identify novel drug combinations in pre-clinical models that could be translated to the clinics.

DNA Damage Response in MaTCL

We are also interested in the cross-talk between JAK-STAT pathway hyperactivation and aberrant DNA damage responses in MaTCL. This is particularly relevant in the T cell prolymphocytic leukemia (T-PLL) disease subtype, where gain-of-function STAT5B mutations significantly co-occur with loss-of-function mutations in ATM, an important DNA damage repair mediator. T-PLL patient samples show increased levels of oxidative stress and DNA damage, and up to 70% of patients harbor mutations within the JAK-STAT pathway. Therefore, we are examining the cooperation between hyperactive JAK-STAT signaling and dysregulated DNA damage responses, with the goal of identifying potential synthetically lethal drug targets or novel combination therapies.

Biomarkers for predicting disease burden and prognosis in MPN

Polycythemia vera (PV), a subtype of myeloproliferative neoplasm (MPN), is a blood disease characterized by an increase in the levels of red blood cells, as well as white blood cells and platelets. 95% of PV patients harbor the activating JAK2V617F mutation, heavily implicating the JAK-STAT pathway in this disease. Thromboembolic events (blood clots) are the major cause of morbidity and mortality in MPN patients, however the molecular mechanisms determining increased risk or incidence of thrombosis in patients remains incompletely understood, and is a currently unmet clinical need. We are therefore using cell lines and mouse models to explore molecular variances in order to define new biomarkers that can be used to stratify patients at higher risk of thrombosis and worse prognosis.

Top left, Image of bone marrow section showing large platelet-producing megakaryocyte cells. Top right, peripheral blood smear stained to show red blood cells, white blood cells and platelets. Bottom, Section showing a blood clot (thrombosis) formed in the lung of a mouse with polycythemia vera (MPN).

Biography

Heidi Neubauer, PhD

Group Leader

E-Mail | ORCID

Heidi Neubauer undertook her doctoral studies in 2012 in biochemistry at the University of Adelaide, Australia, under the supervision of Prof. Stuart Pitson. Her PhD work, based at the Centre for Cancer Biology in Adelaide, focused on identifying mechanisms of cellular transformation and novel functions of oncogenic proteins. After graduating, Dr. Neubauer chose to further develop her expertise in biochemistry and cancer biology by joining the laboratory of Prof. Richard Moriggl in 2017 as a postdoctoral fellow at the University of Veterinary Medicine, Vienna. Here, her research explores oncogenic mechanisms of the JAK-STAT core cancer pathway, particularly in mature T cell leukemia/lymphoma and myeloproliferative neoplasms. Dr. Neubauer is the recipient of several awards including a Vetmeduni Vienna ‘Young Scientist of the Year’ Award (2019), the Royal Adelaide Hospital Medical Staff Society Research Prize (2016), and the ‘David Walsh Prize’ of the Australia and New Zealand Society for Cell and Developmental Biology (2015).

Dr. Neubauer is currently a University Assistant at the University of Veterinary Medicine, Vienna, in the unit of Functional Cancer Genomics. After successfully obtaining project funding through the EU ERA PerMed initiative in 2019, she now oversees her own research team exploring basic and translational cancer research within the Moriggl group.

Top Publications

de Araujo ED*, Erdogan F*, Neubauer HA*, Meneksedag-Erol D et al (2019) Structural and functional consequences of the STAT5BN642H driver mutation. Nature Communications, 10(1): 2517; doi: 10.1038/s41467-019-10422-7. *co-first authors

Neubauer HA, Tea MN, Zebol JR, Gliddon BL et al (2019) Cytoplasmic dynein regulates the subcellular localization of sphingosine kinase 2 to elicit tumor-suppressive functions in glioblastoma. Oncogene, 38(8): 1151-1165; doi: 10.1038/s41388-018-0504-9.

Neubauer HA, Pham DH, Zebol JR, Moretti PAB et al (2016) An oncogenic role for sphingosine kinase 2. Oncotarget, 7(40): 64886-64899; doi: 10.18632/oncotarget.11714.

Neubauer HA and Pitson SM (2017) Validation of commercially available sphingosine kinase 2 antibodies for use in immunoblotting, immunoprecipitation and immunofluorescence. F1000Research, 5: 2825; doi: 10.12688/f1000research.10336.2.

Kadekar D, Agerholm R, Rizk J, Neubauer HA et al (2020) The neonatal microenvironment programs conventional and intestinal Tbet+ γδT17 cells through the transcription factor STAT5. Journal of Clinical Investigation, 130(5): 2496-2508; doi: 10.1172/JCI131241.

Memberships

  • Austrian Association of Molecular Life Sciences and Biotechnology (ÖGMBT)
  • American Association for Cancer Research (AACR) – Associate Member
  • International Cytokine & Interferon Society (ICIS)
  • European Association for Cancer Research (EACR)
  • Australian Society for Biochemistry and Molecular Biology (ASBMB)

Group Members

Marie Ploderer

PhD Student

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Susann Schönefeldt

PhD Student

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Lena Schreiberhuber

Master Student

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Tamara Wais

Master Student

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Funding

ERA PerMed EU-Funded Project

The project “Novel individualized therapies in JAK/STAT driven T cell malignancies” (Acronym: JAKSTAT-Target) aims to investigate the role of the JAK-STAT pathway in mature T cell lymphomas and to identify potential drugs and drug synergies targeting this pathway.

The consortium of six research groups from Vienna (Heidi Neubauer), Helsinki (Satu Mustjoki, Tero Aittokallio), Cologne (Marco Herling) and Toronto (Patrick Gunning, Benjamin Haibe-Kains) will focus on the entities of T cell prolymphocytic leukemia (T-PLL) and T cell large granular lymphocyte leukemia (T-LGLL), both showing a high incidence of missense mutations in JAK-STAT pathway genes.

The consortium, led by Satu Mustjoki, will uncover new mechanistic insights into these rare diseases and implement machine learning algorithms to predict synergistic effects from genomic, clinical and in vitro drug sensitivity data, ultimately integrating these data into clinical trials.

For more details, please visit the JAK STAT Target Consortium website or the ERA Per Med Newsletter.