Dissecting cell type-specific chromatin dynamics driven by oncogenic JAK-STAT signalling

NETWORK CONTRIBUTION

JAK-STAT signalling is vital for the development, survival and response of immune cells. Intriguingly, members of the JAK-STAT pathway are frequently mutated in cancer and are known to drive several haematopoietic malignancies. Based on our observation that key regulatory regions of myeloid development are specifically hypermethylated in the lymphoid lineage, we hypothesize that oncogenic transformation by aberrant STAT activity is dependent on a permissive epigenome.

To identify cell type-specific differences in the response to JAK-STAT signalling, we will isolate specific lymphoid and myeloid cell populations from wild-type and STAT-deficient mice and analyse their epigenome and transcriptome response upon treatment with STAT-activating cytokines. The cross-talk between JAK-STAT signalling and the epigenome will be investigated using in vivo transplants of retrovirally transformed bone marrow harbouring known STAT3 and STAT5 mutations, which will provide a basis for dissecting the epigenome dynamics of oncogenic transformation.

The ensuing insights into STAT-induced oncogenic reprogramming of the epigenome could potentially contribute to the development of precision therapies for STAT-driven leukaemia.

PUBLICATIONS

SFB-F61 / F28 related publications - Group Bock

Kollmann, K., Heller, G., Schneckenleitner, C., Warsch, W., Scheicher, R., Ott, R.G., Schäfer, M., Fajmann, S., Schlederer, M., Schiefer, A.-I., Reichart, U., Mayerhofer, M., Hoeller, C., Zöchbauer-Müller, S., Kerjaschki, D., Bock, C., LKenner, L., Hoefler, G., Freissmuth, M., Green, A.R., Moriggl, R., Busslinger, M., Malumbres, M., and Sexl, V. (2013).
A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis.
Cancer Cell 24: 167-181. doi: dx.doi.org/10.1016/j.ccr.2013.07.012
Milosevic Feenstra, J.D., Nivarthi, H., Gisslinger, H., Leroy, E., Rumi, E., Chachoua, I., Bagienski, K., Kubesova, B., Pietra, D., Gisslinger, B., Milanesi, C., Jager, R., Chen, D., Berg, T., Schalling, M., Schuster, M., Bock, C., Constantinescu, S.N., Cazzola, M., and Kralovics, R. (2016).
Whole exome sequencing identifies novel MPL and JAK2 mutations in triple negative myeloproliferative neoplasms.
Blood 127, 325-332
Pham, H.T.T., Maurer, B., Prchal-Murphy, M., Grausenburger, R., Grundschober, E., Javaheri, T., Nivarthi, H., Boersma, A., Kolbe, T., Elabd, M., Halbritter, F., Pencik, J., Kazemi, Z., Grebien, F., Hengstschlager, M., Kenner, L., Kubicek, S., Farlik, M., Bock, C., Valent, P., Muller, M., Rulicke, T., Sexl, V., and Moriggl, R. (2018).
STAT5BN642H is a driver mutation for T cell neoplasia.
J Clin Invest 128, 387-401

TEAM