Max-Eder-Research Group Pabst
"Identification of leukemia propagating genetic networks in primary human leukemic stem cells”
Previous and current research
Despite increasing use of targeted therapies in the treatment of acute myeloid leukemia (AML) long term survival is rare in particular in elderly patients. Development of next generation sequencing (NGS) technologies providing detailed information on genetic lesions present in tumor genomes has improved risk stratification and paves the way for personalized therapy. Nonetheless, especially patients with high risk mutations often do not benefit from aggressive therapy regimens, which bear themselves the risk of treatment related mortality.
One major cause of relapse in AML is supposed to be the lack of therapies that permanently eradicate leukemia stem cells (LSCs). When human AML patient cells are transplanted into immunocompromised mice only a small fraction of cells is able to home to the bone marrow and recapitulate the human disease. These cells are called leukemia initiating, leukemia propagating, or leukemia stem cells. LSCs are considered to be the cause of relapse of the disease. They share certain features with normal hematopoietic stem cells such as higher resistance to chemotherapy and the capacity to self-renew. Due to these characteristics it is obvious that only efficient eradication of these LSCs will lead to long-term disease free survival. Our group aims to understand the similarities and differences between normal and malignant stem cells and to use this knowledge to develop more efficient therapies for AML patients.
Medizinische Klinik, Abt. Innere Medizin V
Hämatologie, Onkologie, Rheumatologie
Im Neuenheimer Feld 410, F02, R607
- Guy Sauvageau (Leucégène Team), IRIC, Montreal, Kanada
- Fréderic Barabé, Quebec City, Kanada
- George Vassiliou, Cambridge, UK
- Jörg Hamann, GPCR consortium, Amsterdam, Niederlande
- Xianhua Piao, Boston, USA
- Claudia Waskow, Dresden
- Keith Humphries, Vancouver, Kanada
Despite increasing use of targeted therapies in the treatment of acute myeloid leukemia (AML) long term survival is rare in particular in elderly patients. Development of next generation sequencing (NGS) technologies providing detailed information on genetic lesions present in tumor genomes has improved risk stratification and paves the way for personalized therapy. Nonetheless, especially patients with high risk mutations such as mutations in the tumor suppressor gene TP53 often do not benefit from aggressive therapy regimens, which bear themselves the risk of treatment related mortality.
Our aim ist o identify specific gene networks in AML with high molecular genetic risk using NGS technology, proteomics and in vivo models.
Leukemics Stem Cells (LSCs) can be distinguished from non-LSC blasts by their potential to engraft immunocompromised mice, in which they reinitiate the human disease. As they are supposed to be the cause of chemoresistance and relapse their eradication is a prerequisite for long term therapy success.
Fig. 1: Primary AML patients cells maintain their immature morphology in presence of optimized culture conditions (shown here day 4 in culture).
Our methods comprise in vitro manipulation of primary human AML cells and healthy hematopoietic stem cells, which we isolate from human cord blood. To avoid rapid differentiation upon in vitro culture we have optimized culture conditions for primary human cells including the use of small molecule (Fig. 1).
We knockdown and overexpress genes in primary cells using lentiviral transduction. Furthermore, the use of xenotransplantation models (NSG, NRGS mice) still represents the gold standard to assess stem cell activity.
With these approaches we aim to better understand the biology of normal and malignant stem cells and to develop more efficient therapies for AML patients.
Medical students searching for a project can send their application to caroline.pabst(at)med.uni-heidelberg.de.
Max-Eder-Research Group Members
Working in the lab
- Lin, H. H., C. C. Hsiao, C. Pabst, J. Hérbert, T. Schöneberg, J. Hamann. 2017. Adhesion GPCRs in regulating immune responses and inflammation. Adv. Immunol., (in press).
- F. Zhou, Y. Liu, C. Rohde, C. Pauli, D. Gerloff, M. Köhn, D. Misiak, N. Bäumer, C. Cui, S. Göllner, T. Oellerich, H. Serve, M.P. Garcia-Cuellar, R. Slany, J. P. Maciejewski, B. Przychodzen, B. Seliger, H.-U. Klein, C. Bartenhagen, W. E. Berdel, M. Dugas, M. M. Taketo, D. Farouq, S. Schwartz, A. Regev, J. Hébert, G. Sauvageau, C. Pabst, S. Hüttelmaier, C. Müller-Tidow. AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukemia. Nature Cell Biology (2017) NCB-M31790B.
- Garg S, Reyes-Palomares A, He L, et al. Hepatic leukemia factor is a novel leukemic stem cell regulator in DNMT3A, NPM1, and FLT3-ITD triple-mutated AML. Blood. 2019;134(3):263–276.
- Göllner S, Oellerich T, Agrawal-Singh S, Schenk T, Klein HU, Rohde C, Pabst C, Sauer T, Lerdrup M, Tavor S, Stölzel F, Herold S, Ehninger G, Köhler G, Pan K-T, Urlaub H., Serve H, Dugas M, Spiekermann K, Vick B, Jeremias I, Berdel WE, Hansen K, Zelent A, Wickenhauser C, Müller LP, Thiede C & Müller-Tidow C. Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia. Nature Medicine. 2016.
- C Pabst, A Bergeron, VP Lavallee, J Yeh, P Gendron, GL Norddahl, J Krosl, I Boivin, E Deneault, J Simard, S Imren, G Boucher, K Eppert, T Herold, SK Bohlander, K Humphries, S Lemieux, J Hebert*, G Sauvageau*, and F Barabe*. GPR56 identifies primary human acute myeloid leukemia cells with high repopulating potential in vivo. Blood (2016). doi:10.1182/blood-2015-11-683649
- Lavallée V-P, Krosl J, Lemieux S, Boucher G, Gendron P, Pabst C, Boivin I, Marinier A, Guidos CJ, Meloche S, Hébert J, and Sauvageau G. Chemo-genomic interrogation of CEBPA mutated AML reveals recurrent CSF3R mutations and subgroup sensitivity to JAK inhibitors. Blood (2016). doi:10.1182/blood-2016-03-705053Polprasert C, Schulze I, Sekeres MA, Makishima H, Przychodzen B, Hosono JA, Padgett RA, Gu X, Phillips JG, Clemente M, Parker Y, Lindner D, Dienes B, Jankowsky E, Saunthararajah Y, Du Y, Oakley K, Nguyen N, Mukherjee S, Pabst C, Godley LA, Churpek JE, Pollyea DA, Krug U, Berdel WE, Klein H, Dugas M, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Yoshida K, Ogawa S, Muller-Tidow C, and Maciejewski JP. Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms. Cancer Cell 27, 658–70 (2015).
- Pabst C, Krosl J, Fares I, Boucher G, Ruel R, Marinier A, Lemieux S, Hebert J, Sauvageau G. Identification of small molecules that support human leukemia stem cell activity ex vivo. Nat Meth 11, 436–442 (2014).
- Lehnertz B, Pabst C, Su L, Miller M, Liu F, Yi L, Zhang R, Krosl J, Yung E, Kirschner J, Rosten P, Underhill TM, Jin J, Hebert J, Sauvageau G, Humphries K, Rossi F. The methyltransferase G9a regulates HoxA9-dependent transcription in AML. Genes & Development 28, 317–327 (2014)
- Bordeleau M, Chagraoui J, Aucagne R, Girard S, Mayotte N, Bonneil E, Thibault P, Pabst C, Bergeron A, Barabé F, Hébert J, Sauvageau M, Boutonnet C, Meloche S, Sauvageau G. UBAP2L is a novel BMI1-interacting protein essential for hematopoietic stem cell activity. Blood (2014). doi:10.1182
- Pabst C, Schirutschke H, Ehninger G, Bornhauser M, Platzbecker U. The graft content of donor T cells expressing gamma delta TCR+ and CD4+foxp3+ predicts the risk of acute graft versus host disease after transplantation of allogeneic peripheral blood stem cells from unrelated donors. Clin. Cancer Res. 13, 2916–2922 (2007).
For full list of publications visit http://materiale-textkulturen.academia.edu/CarolinePabst