tailieunhanh - Hematologic Malignancies: Myeloproliferative Disorders - part 2

Cơ chế đằng sau sự hình thành của bất thường di truyền tế bào trong các tế bào Ph-âm không rõ ràng. Mặc dù chúng ta có thể không chính thức loại trừ rằng imatinib có thể được trực tiếp hoặc gián tiếp chịu trách nhiệm về những bất thường | 28 Chapter 2 Bcr-Abl and Signal Transduction atinib treatment was that karyotypic abnormalities were detectable in the Ph-chromosome negative cells of some 5-10 of these patients and that this phenomenon in a minority of cases was also associated with myelodysplastic features Alimena et al. 2004 Bumm et al. 2003 Deininger 2003 Goldberg et al. 2003 Loriaux and Dei-ninger 2004 Medina et al. 2003 O Dwyer et al. 2003 Terre et al. 2004 . Interestingly these cytogenetic abnormalities are not random and are similar to those such as trisomy 8 monosomy 7 and del 20q found associated with CML progression in the Ph-positive clone Andersen et al. 2002 Loriaux and Deininger 2004 . The mechanism behind the formation of cytogenetic abnormalities in Ph-negative cells is unclear. Although we cannot formally exclude that imatinib may be directly or indirectly responsible for these abnormalities it must be underlined that the same findings have been also reported in patients treated with interferon-alpha Casali et al. 1992 Fayad et al. 1997 Izumi et al. 1996 . The lower incidence of the phenomenon observed in the latter cases could be simply due to the fact that the interferon-alpha antiproliferative effect being much less Bcr-Abl-specific than that of imatinib could have also suppressed most of the Ph-negative clones in addition to the Ph-positive cells. Therefore the possible scenario is that imatinib simply unmasks the presence of clones with Ph-negative cytogenetic abnormalities and that these may represent the consequence of a diffuse damage to the hematopoietic compartment or the collateral progeny of an abnormal stem cell with a predisposition to acquire additional mutations including the formation of a Ph chromosome Loriaux and Deininger 2004 . According to this hypothesis the t 9 22 translocation is not the primary but a subsequent event in the pathogenesis of CML. This model for CML development had been proposed several years ago by Fialkow and his coworkers based on the .