The impact of AML - stromal cell interaction on malignant transformation, maintenance of leukemic stem cells and drug resistance

• Applicant: Professor Dr. Thomas Kindler
• Subject Area: Hematology, Oncology
• Term: from 2010 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 161794070

Based on our current understanding of leukemogenesis, it is believed that the leukemic clone is perpetuated by a rare population of leukemia stem cells (LSC). These LSCs share many characteristics with normal hematopoietic stem cells (HSCs), such as phenotpype, self renewal potential, a quiescent cell cycle status and enhanced drug resistance. Whereas cytotoxic drugs eradicate actively cycling leukemic blasts, they often do not target LSCs, embed in their niche and protected against drug induced apoptotic cell death. Recent studies indicate, that the hematopoietic microenvironment or stem cell niche dictates stem cell quiescence, lack of motility and expression of anti-apoptotic proteins, which may result in refractory disease or relapse, a major concern in cancer therapy. Therefore, disruption of specific LSC – stroma cell interactions might drive this leukemia-maintaining cell population into cell cycle and make these cells vulnerable to chemotherapy. For this proposal, we already performed a global gene expression screen in stromal feeder layer cells upon co-culture with highly enriched LSCs or HSCs. Several interesting genes, such as receptor/ligands, extracellular matrix components or know oncogenes, were differentially regulated in stromal cells cultured with LSCs compared to HSCs. In this proposal, we will further analyse these genes in the context of LSCs – stromal cell interaction and functionally characterize the effect on LSC maintenance and development of drug resistance. Promising candidate genes will be further evaluated in murine in vivo models.

• DFG Programme: Research Grants