Multistep Versus Singlestep Pathogenesis

It is generally thought that Bcr-Abl alone is necessary and sufficient to induce the chronic phase of CML. This notion is supported by murine disease models (see below), the ability of certain therapies to restore Ph-negative polyclonal hematopoiesis,35 5152 and the lack of detectable genetic abnormalities in addition to the Ph chromosome in newly diagnosed patients. However, there are some arguments against this view. Mathematical modeling suggested that the epidemiology of chronic phase CML is more compatible with two or three genetic events than with one.53 X-chromosome-based clonality studies in Ph-negative Epstein-Barr-virus-transformed B-cell lines from CML patients showed evidence for "skewing" toward the genotype of the leukemia clone in a subset of patients, consistent with a clonal abnormality that predated the acquisition of the Ph chromosome.54 Lastly, BCR-ABL mRNA is detectable at very low levels in the blood of many healthy individuals, suggesting that Bcr-Abl alone may not be sufficient to induce the CML phe-notype.55 56 Another observation pointing to the possibility of a pathological "pre-Philadelphia" state is the observation of cytogenetic abnormalities in the

Ph-negative cells of some patients, with a cytogenetic response to imatinib.35'5758 Although in the vast majority of cases the respective abnormalities, many of them typical of myelodysplastic syndromes, are not present in Bcr-Abl-positive cells, arguing against the acquisition of Ph as a secondary event, it remains possible that the Ph-negative hematopoiesis as a whole is abnormal. In this scenario, different abnormal clones would emerge, including the Bcr-Abl-positive clone that has the greatest proliferation capacity and leads to clinical CML.

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