The biology of ageing in relation to acute myeloid leukemia (AML) in older patients

Acute myeloid leukemia (AML) is a malignant blood disorder. AML occurs in all
ages, but mainly in elderly patients (>60 years). The last decade a lot of
progress has been made in the treatment results. However, only patients younger
than 60 years have benefited. Because of differences in clinical
characteristics (eg inherent chemotherapy resistance) and biological
characteristics (eg the occurence of complex aberrant karyotypes) in AML in
elderly patients, AML in elderly is considered to be a different disease. The
lack of molecular data to explain these differences between AML in elderly and
AML in younger patients, has motivated us to compare gene expression profiles
of AML cells of young and elderly patients. This research showed that there are
indeed molecular (= gene expression) differences between AML cells of younger
and elderly patients. A striking gene was p16, which expression was lower in
AML cells of elderly patients, while during normal ageing of healthy
hematopoietic stem cells the expression increases with age. It is even
pressumed that the higher expression of p16 during ageing plays an important
role to 'expand' damaged stem cells so that these cannot cause a malignant
disease anymore. As a result the number of functional stem cells decreases as
well as regeneration capacity of the different tissues. So the higher
expression of p16 during ageing protects us from cancer, caused by accumulation
of DNA damage and proteins during ageing, with ageing as a result. From this
perspective the lower expression of p16 in AML cells of elderly patients with
respect to younger patients, suggests that the elimination of mechanisms that
protect us from accumulation of DNA damage (such as higher expression of p16),
are necessary to develop leukemia in old stem cells.
The aim of this study is to attain more insight in the relation between ageing
and cancer. In the first place we want to compose a list of genes, besides p16,
that play a specific role in the development of AML in elderly patients. In
subsequent experiments we wil show the biological interest of these genes in
CD34+ healthy and AML cells. Further, we would like to understand why the
introduction of a certain oncogene in a young stem cell has other consequences
than the introduction of this oncogene in an old stem cell. Technically we can
achieve this by infecting old and young hematological stem/precursor cells with
viruses containing a certain cancer gene.

The aim of the study is to:
1. Attain more insight in the biology of ageing of hematopoietic stem cells
2. Attain more insight in the relation between ageing and cancer

See chapter 4 and 5 protocol.

Risks for participants in this study are:
1. For older individuals undergoing a total hip replacement the surgery will be
a few minutes delayed.
2. For volunteers younger than 35 years of age and the healthy potential donors
no risks are expected.
3. Bleeding due to bone marrow aspirate is NOT an expected problem