Influences of hypoxic conditions in the bone marrow concerning the behaviour and maintenance of chronic myeloid leukemic stem cells

• Applicant: Dr. Deniz Gezer
• Subject Area: Hematology, Oncology
• Term: from 2011 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 201007619

Self renewal and multipotency are the hallmark for stem cells. The best characterized stem cell system is the hematopoietic stem cell (HSC) system. Like any other stem cell the HSC needs a special niche in which they have special conditions to habour their abilities and they are protected from external influences.HSC can be classified into short term (ST-HSC) and long term HSC (LT-HSC). LT-HSC are located near to the endosteum and normally do not enter cell cycle. While ST-HSC are located near to the blood vessels and the sinuids and normally lost their quiescence, start to proliferate and differentiate and therefor lose their multipotency and stemness.The HSC niche is defined by a low oxygen concentration (0,1 to 1 %) also called hypoxic condition. This low concentration of oxygen is essential for habouring the stem cell status by maintenance and quienscense. Studys showed that hypoxia-induceable-factor (HIF) is stabilized at oxygen levels around 1% and lower, and leads to inhibition of cyclin dependent kinases (CDKs). There are a lot of other important factors in regulation of HSC (like FoxO proteins, Rb, WNT, BmiI, cytokines) but there is no doubt, that hypoxia and its direct targets are key players. Leukemic stem cells (LSC) also have their special niches and use the conditions to be secured from therapeutic agents. Another interesting field to be elucited is the controversial role of autophagy. While HSC use autophagy to be protectec from DNA damage, LSCs especially chronic leukemia stem cells rescue by autophagy from treatment with tyrosin-kinase inhibitors (TKIs). Hypoxia plays a role in inducing autophagy at levels below 0,1 % and therefore might play a role in not only habouring HSC but also leukemic stem cells.We try to search for regulators of HIF-1 and other key regulators in hypoxia and try to find out differences mechanisms betwenn HSC and LSC. The results of our studys should eluciate these mechanisms in the behaviour of HSC and LSC.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Dr. Kamil R. Kranc