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Chronic Myelomonocytic Leukemia

As a consequence of a reciprocal t(5;12) chromosomal translocation, the trans-membrane and the intracellular domains of the PDGFRb gene are fused to various partners like TEL (ETV6) (Golub et al. 1994), H4/D10S170 (Schwaller et al. 2001), HIP1(Ross et al. 1998) and RAB5 (Magnusson et al. 2001) all of which encode putative oligomerization domains. The resulting constitutive activation of the PDGFRb kinase generates a myeloproliferative disorder which is characterized by eosinophilic leukemia or CMML (Steer and Cross 2002), a subtype of the myelodysplastic syndrome which may progress to an acute leukemia. STI571 not only inhibited the in vitro proliferation of cells transformed by these oncoproteins (Beran et al. 1998; Sjöblom et al. 1998) but has also displayed antitumor activity in vivo in a bone marrow transplantation model driven by TEL-PDGFRb (Tomasson et al. 1999). STI571 treatment led to a normalization of eosinophils and peripheral blood cells in CMML patients involving PDGFRb translocations (Apperley et al. 2002; Magnusson et al. 2002).

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