Applications of DNA Microarray Technology in Cancer Research - DNA Microarray Technology and Data Analysis in Cancer Research - page 14

The Abl tyrosine kinase inhibitor STI571 (imatinib mesylate; Gleevec)
has become the most effective drug for leukemia therapy, and has been
shown to induce a complete hematologic response in all interferon-resistant
chronic-phase CML patients (Druker et al ., 2001b). However, STI571 was
unable to abrogate BCR-ABL-expressing leukemic cells (Marley et al .,
2000) and induced cellular and clinical drug resistance (Branford et al .,
2002; Gorre et al ., 2001; le Coutre et al ., 2000; Mahon et al ., 2000; Shah et
al ., 2002; von Bubnoff et al ., 2002; Weisberg and Griffin, 2000), suggest-
ing that the use of STI571 as a single agent may not prevent eventual dis-
ease progression to terminal blast crisis or cure CML. Moreover, STI571 is
much less effective in treating CML blast crisis patients (Druker et al .,
2001a; Talpaz et al ., 2000). Therefore, the development of new therapeutic
drugs that are synergistic with available treatment strategies is critical.
The success of this approach requires an understanding of the signaling
pathways utilized by BCR-ABL to induce CML and B-ALL. Expression
of BCR-ABL has been shown to activate multiple signaling molecules/
pathways, including Ras, MAPK, STAT, JNK/SAPK, PI-3 kinase, NF- B,

and c-MYC (Sawyers, 1997), as well as cytokine production (Anderson and
Mladenovic, 1996; Hariharan et al ., 1988). Recent studies also link BCR-
ABL to apoptotic pathways (Amarante-Mendes et al ., 1998; Dubrez et al .,
1998; Goetz et al ., 2001; Honda and Hirai, 2001; Jonuleit et al ., 2000;
Majewski et al ., 1999; McGahon et al ., 1995; Neshat et al ., 2000; Parada
et al ., 2001; Sanchez-Garcia and Martin-Zanca, 1997; Skorski et al ., 1997;
Skorski et al ., 1996) and to the activation of Src kinases in cultured cells
(Danhauser-Riedl et al ., 1996; Lionberger et al ., 2000; Warmuth et al .,
1997). Our studies in mice have shown the involvement of three Src family
kinases — Lyn, Hck, and Fgr — in BCR-ABL-induced B-lymphoid
leukemia (Hu et al ., 2004). It is important to point out that, although these
signaling molecules are present and activated in BCR-ABL-expressing
cells, it remains unclear what role, if any, they play in the development of
BCR-ABL-induced leukemias. The physiological relevance of the in vitro
findings of the roles of signaling molecules in BCR-ABL signaling is better
addressed in vivo using the mouse leukemia model, although in vitro stud-
ies (such as the use of cultured cells or cell lines) are often useful in finding
preliminary clues.

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