Genetic lesions and the malignant phenotype of haematological cancers

Cancer in a patient usually becomes manifest as a process of excessive cell growth in one or more organs which, if uncontrolled, will ultimately lead to death of the patient. The malignant clinical phenotype of cancer is the reflection of the altered cellular behaviour of individual cancer cells. Cumulative genetic alterations in pathways controlling cellular growth or survival, endow the latter cells with the capacity to grow independently of growth-regulating signals, to resist programmed cell death, to divide endlessly, and to interact differently with non-malignant cellular environment. The discovery of such recurrent genetic aberrations in haematological malignancies has led to new diagnostic tests, but also to a shift towards development of new rational, specific and effective targets for therapy. For instance, protein tyrosine kinases are pivotal switches for growth control, and small molecule inhibitors have profoundly reshaped therapeutic practice in in myeloproliferative disorders or acute lymphoblastic leukemias. New targets however also encompass the detrimental interactions of malignant cells with the normal environment, e.g. the immune system in the myelodysplastic syndromes. Finally, the paradigm of cancer as the result of cumulative genetic damage in normal cells also sheds new light on the vulnerability of congenital bone marrow failure syndromes to develop haematological malignancies. In this paper, we review our recent contributions to this cancer paradigm in malignant or premalignant haematological conditions.