Studying leukemia with novel patient-derived iPSC-based models

• Applicant: Dr. Josephine Wesely
• Subject Area: Hematology, Oncology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 390370981

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, which develops through the acquisition of gene mutations in normal hematopoietic stem and progenitor cells (HSPCs) residing in the bone marrow. Recently, next generation sequencing technology enabled a detailed and comprehensive description of the set of mutations found in AML patients (mutational landscape of AML) and the clonal evolution of this disease. This wealth of genetic information now available can be leveraged towards a better understanding of the pathogenesis of this disease and the development of better targeted therapies. While functional interrogation of the effects of driver mutations in myeloid malignancies has mostly used mouse models so far, the latter also have certain limitations, related to differences in regulation of hematopoiesis and oncogenesis between mice and humans. The host laboratory, Dr Papapetrou’s laboratory, has pioneered the development of models of myeloid malignancies using patient-derived induced pluripotent stem cells (iPSCs). Dr Papapetrou’s laboratory and, independently, Dr Majeti’s laboratory at Stanford, recently showed that reprogramming of human AML cells into iPSCs is feasible and that hematopoietic cells derived from them upon differentiation exhibit leukemic properties, such as extended in vitro proliferation, differentiation block, engraftment of a leukemia-like disease into immunodeficient animals and leukemic gene expression. These new models offer unprecedented opportunities to study AML “in-a-dish” and in vivo in xenografts to investigate the cellular and molecular mechanisms leading to AML and identify new therapeutic targets. In this application, I propose to advance this line of research using these very novel AML-iPSC models. Therefore I will generate iPSC lines from AML patients with diverse genotypes (Aim 1). Secondly, I will characterize the hematopoiesis derived from AML-iPSC lines in vitro (Aim 2) and lastly investigate the in vivo engraftment potential (Aim 3).

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Eirini Papapetrou, Ph.D.