The acute leukemias continue to present a formidable challenge for which there is not yet a reliably curative 'standard approach' for the majority of adults with this family of diseases. In order to make progress in terms of curing these devastating diseases, we must understand leukemia biology on the clinical, cellular and molecular levels, with exploitation of the leukemia-associated molecular targets in designing strategies aimed at eradicating the leukemic clone. In this review, we will discuss a few key mechanisms of leukemogenesis that represent convergent pathways of malignant transformation and, as such, present pivotal molecular targets for therapy. Specifically, we focus on normal and leukemic hematopoietic cell cycle regulation, issues surrounding DNA damage and repair, programmed cell death (apoptosis) and drug responsiveness, and multidrug resistance as a marker for stem cell involvement and as a novel target for intervention. When functioning normally, such mechanisms determine a cell's ability to respond to DNA damage, traverse the cell cycle and maintain genomic integrity. And in addition to the target cell itself, there are crucial extracellular determinants of hematopoietic cell proliferation and differentiation that modulate net signalling activity and gene expression, cell-cell contact and growth-modulating factors for instance. The molecular dissection of these intersecting pathways, from the extracellular milieu to the genes themselves, in both the normal and transformed states will elucidate the means by which cells escape treatment-induced death. Such understanding should, in turn, lead to the development of targeted therapeutic strategies that exploit differences between normal and malignant cells, overcome the mechanisms by which leukemic cells acquire drug resistance, and enhance the curability of these devastating diseases.

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