الفهرس | Only 14 pages are availabe for public view |
Abstract Acute leukemia occurs as a result of accumulation of genetic mutations in the cellular genes whose products affect specific cellular regulatory mechanisms as growth factor receptor function, signal transduction and gene transcription. As a consequence, these processes may dysregulate critical biological functions, in particular the capabilities of proliferation, differentiation and apoptosis. The search for the targets of the oncogenic events has indicated various mechanisms that may lead to leukemia. Two types of genetic alterations have been demonstrated. Some genes when mutated gain growth stimulatory functions (proto-oncogenes), promoting leukemo-genesis, while others lose their growth inhibitory activity (tumor suppressor genes). The diagnosis and further classification of acute leukemia requires full assessment of the medical history, family history, physical findings and careful assessment of cytological features in blood and bone marrow. The use of cytochemistry is selective and the application of immunophenotyping can be selective but is tending to become universal when facilities are readily available. Ideally, cytogenetic analysis should be universally applied with molecular analysis. The variability of clinical courses within certain subgroups is at least in part due to deeper insights into coincidences of the chromosomal and molecular aberrations that might help in treatment, eg. RARα oncogene which is involved in APL is associated with good prognosis when linked to PML oncogene and bad prognosis with PLZF oncogene when treated with ATRA, also there is NPMc+ AML with distinctive genetic, biological and clinical features, that should be included as a separate AML entity in the upcoming version of WHO classification. In ALL, NOTCH1 mutations present in patients with T-ALL indicated poor prognosis and combining GSI(γ secretase inhibitors) with kinase inhibitors or dexamethasone could potentially enhance the anti-proliferative effects of GSI on leukemic cells, which may improve their application as agents for the treatment of T-ALL expressing mainly NOTCH1. |