Stimulated differentiation of native human acute myeloid leukemia (AML) blasts as a potential cancer-cell specific therapeutic target

Acute myeloid leukemia (AML) is an aggressive disorder characterized by accumulation in the bone marrow of large numbers of abnormal blood cells that fail to develop into normal functional blood cells. This is a life-threatening condition if not treated. Patients under the age of 60 are given intensive cytotoxic treatment, but the five year survival after diagnosis of AML is below 20 %. Most patients diagnosed with AML are above 60 years, and there is a need for newer and more effective and targeted treat ments with acceptable side. The present project primarily aims at stimulating the halted maturation of native human AML progenitors. Clinically, differentiation-stimulating treatment with a combination of all-trans retinoicacid (ATRA)+valproat+theophyllam ine will be given to patients and the expression of differentiation associated membrane molecules and phosphorylation status of intracellular signal transduction pathways will be characterized. The effect of this treatment will be characterized in detail both on leukemic and normal bloodcells. Experimental studies will elucidate further the degree of apoptosis, proliferation, cell cycle and differentiation (morphologic and certain immunologic markers), known signal transduction pathways (protein- and lipi d phosphorylation, tumor suppressor gene products. The balance between the two gene-expression regulating enzymes histone deacetylase (HDAC) and DNA methyltransferase (DMT) by inhibitors is a potential target for treatment of cancer cells and the combinat ion of HDAC and DMT inhibitors (with or without growth factors) is very effective in inducing differentiation, apoptosis, and/or growth arrest in leukemia. We will investigate the effect of these inhibitors on differentiation for a large group of native A ML blasts and xenograft models (NOD/SCID) with regard to proliferation, apoptosis, markers for normal hematopoietic progenitor differentiation and cellular signaling processes that might be affected.