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Hypereosinophilic Syndrome

HES is characterized by persistent eosinophilia that can result in damage to various organs (Weller and Bubley 1994). Clinical studies with STI571 have reported responses in HES patients that were associated with normalization of eosinophil counts (Gleich et al. 2002, 2003). About 50% of the HES patients with durable responses to STI571 were found to have a FIP1L1-PDGFRa fusion oncogene which harbors a constitutively activated PTK activity (Cools et al. 2003a; Griffin et al. 2003). This oncogenic FIP1L1-PDGFRa was also found in patients with systemic mastocytosis that have been found to respond to the STI571 treatment (Pardanani et al. 2003). Other genetic abnormalities resulting in the activation of a "putative STI571 sensitive protein kinase" are likely to be responsible for the responses observed in FIP1L1-PDGFRa-negative HES patients that have been treated with STI571. Interestingly, one HES patient with FIP1L1-PDGFRa which relapsed

Fig. 2a-d STI571 binding to Abl, Kit, and PDGFRb. a Hydrogen bonds between STI571 and Abl, Kit, or PDGFRb. Hydrogen bonds between STI571 and the key residues in Abl, Kit, and PDGFRb involve: anilino-NH of STI571 with T315 of Abl, T670 of Kit, or T681 of PDGFRb; amide-NH of STI571 with E286 of Abl, E640 of Kit, or E651 in PDGFRb; amide-carbonyl of STI571 with D381 of Abl, not to D810 of Kit, but possibly to D844 of PDGFRb (D of the DFG motif N-terminal A-loop); pyridine N of STI571 with to M318 of Abl, C673 of Kit, or C684 in PDGFRb; N-methylpiperazine of STI571 with I360/H361 of Abl, I789/H790 of Kit, or I823/H824 in PDGFRb. b STI571 binding to Abl. Details of the

Fig. 2a-d STI571 binding to Abl, Kit, and PDGFRb. a Hydrogen bonds between STI571 and Abl, Kit, or PDGFRb. Hydrogen bonds between STI571 and the key residues in Abl, Kit, and PDGFRb involve: anilino-NH of STI571 with T315 of Abl, T670 of Kit, or T681 of PDGFRb; amide-NH of STI571 with E286 of Abl, E640 of Kit, or E651 in PDGFRb; amide-carbonyl of STI571 with D381 of Abl, not to D810 of Kit, but possibly to D844 of PDGFRb (D of the DFG motif N-terminal A-loop); pyridine N of STI571 with to M318 of Abl, C673 of Kit, or C684 in PDGFRb; N-methylpiperazine of STI571 with I360/H361 of Abl, I789/H790 of Kit, or I823/H824 in PDGFRb. b STI571 binding to Abl. Details of the under STI571 treatment was found to contain a T674I point mutation in the kinase domain of the PDGFRa, which corresponded to a STI571-resistant mutation (T315I) found in Bcr-Abl (Cools et al. 2003b; Fig. 2). The STI571-resistant FIP1L1-PDGFRa-T674I mutant was sensitive to another PDGFR inhibitor, PKC412, which targets a different conformation of the PDGFRa kinase domain compared to STI571 (Cools et al. 2003b).

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