Fusion Tyrosine Kinases Induce Drug Resistance by Stimulation of Homology-Dependent Recombination Repair, Prolongation of G₂/M Phase, and Protection from Apoptosis

Abstract

Chromosomal translocations are responsible for the appearance of oncogenes encoding fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGF␤R, TEL/TRKC(L), and NPM/ALK (6, 35). BCR/ABL is derived from relocation of the portion of the c-ABL gene from chromosome 9 to the portion of the BCR gene locus on chromosome 22 [t(9;22)] and is present in most chronic myelogenous leukemia (CML) patients and a cohort of acute lymphocytic leukemia (ALL) patients (11,19,64). TEL/ABL results from a t(9;12) translocation reported in ALL, acute myelogenous leukemia (AML), and atypical CML (35) and consists of the amino-terminal fragment of the TEL domain fused in-frame with exon 2 of ABL (24). TEL/JAK2 was characterized as a product of a t(9;12) translocation which includes the TEL oligomerization domain and JAK2 catalytic domain (37) and was found in ALL (37, 51). TEL/PDGF␤R is associated with a t(5;12) translocation which juxtaposes the amino-terminal region of TEL with the transmembrane and tyrosine kinase domains of the platelet-derived growth factor receptor ␤ (23). TEL/PDGF␤R was found in chronic myelomonocytic leukemia (35). The consequence of t(12;15) is expression of the TEL/TRKC fusion tyrosine kinase associated with AML, infantile fibrosarcoma, and congenital mesoblastic nephroma (41). The TEL/TRKC fusion in AML [TEL/TRKC(L)] includes exons 1 to 4 of the TEL gene fused in frame to the tyrosine kinase domain of TRKC lacking a 42-bp exon near the C terminus of the TRKC moiety. NPM/ALK, formed by the t(2;5) translocation, was implicated in the pathogenesis of anaplastic large cell lymphoma (38). The NPM/ALK fusion gene encodes a 75-kDa hybrid protein that contains the aminoterminal portion of the nucleolar phosphoprotein nucleophosmin (NPM) joined to the entire cytoplasmic portion of the receptor tyrosine kinase ALK (anaplastic lymphoma kinase) (44). These FTKs (BCR/ABL-related FTKs) show structural similarities, which include an amino-terminal oligomerization domain responsible for constitutive oligomerization and activation of the associated tyrosine kinase of the carboxy-terminal fusion partner.FTKs and other oncogenic tyrosine kinases such as v-Src and HER-2/neu activate multiple signaling pathways responsible for protection from apoptosis, induction of growth factor-independent proliferation, transformation, and resistance to therapeutic drugs and to ␥-radiation (25,41,43,53,54,61,85). Resistance to DNA-damaging agents is a cause for failure in the therapy of human cancer, including hematological malignancies. Several mechanisms of resistance to DNA damage

Fusion tyrosine kinases: a result and cause of genomic instability

“…FTKs display common and unique characteristics of activation of these pathways; for example, PI-3k is stimulated by all FTKs listed above, whereas STAT5 and PLCg seem to be activated by the BCR/ABL-related FTKs, with exception to TEL/TRKC (Liu et al, 2000;Nieborowska-Skorska et al, 2001;Slupianek et al, 2002;Baumann et al, 2003). In addition, leukemogenic properties of TEL/ABL seem to be distinct from those of BCR/ABL (Million et al, 2002).…”

“…Drug resistance BCR/ABL and related FTKs such as TEL/ABL TEL/ PDGFbR, TEL/JAK2 and NPM/ALK demonstrate an enhanced ability to survive genotoxic stress probably owing to enhanced DNA repair, prolonged S and G 2 /M checkpoints for extended repair and inhibition of proapoptotic pathways (Bedi et al, 1995;AmaranteMendes et al, 1998;Skorski, 2002;Slupianek et al, 2002Slupianek et al, , 2006Canitrot et al, 2003;Lauren et al, 2003;Nieborowska-Skorska et al, 2006) (Figure 3). These three factors may work in concert to provide the necessary protection from DNA damage-induced apoptosis.…”

“…The former mechanism involves RAD51-driven invasion and pairing of a single-stranded DNA to the homologous template. Elevated levels of RAD51 have been observed in various tumors and positively associated with genotoxic therapy resistance (Vispe et al, 1998;Collis et al, 2001;Raderschall et al, 2002;Slupianek et al, 2002Slupianek et al, , 2006. Leukemias and lymphomas expressing BCR/ABL-related FTKs, such as TEL/ABL, TEL/ PDGFbR, TEL/JAK2, NPM/ALK and ZNF198/ FGFR1, display elevated levels of RAD51 and enhanced HRR activity (Slupianek et al, , 2002Heath and Cross, 2004).…”

“…Elevated levels of RAD51 have been observed in various tumors and positively associated with genotoxic therapy resistance (Vispe et al, 1998;Collis et al, 2001;Raderschall et al, 2002;Slupianek et al, 2002Slupianek et al, , 2006. Leukemias and lymphomas expressing BCR/ABL-related FTKs, such as TEL/ABL, TEL/ PDGFbR, TEL/JAK2, NPM/ALK and ZNF198/ FGFR1, display elevated levels of RAD51 and enhanced HRR activity (Slupianek et al, , 2002Heath and Cross, 2004). Although Deutsch et al (2001) indicated that DNA-PKcs, an important kinase in NHEJ, may be downregulated in CML cells, subsequent reports employing various in vitro and in vivo methods detected enhanced activity of NHEJ in BCR/ABLtransformed leukemia cells and CML patient cells (Gaymes et al, 2002;Brady et al, 2003;Nowicki et al, 2004;Slupianek et al, 2006).…”

“…FTKs may stimulate antiapoptotic proteins such as BCL2 and BCL-X L and inhibit proapoptotic proteins BAD and BAX, thus preventing the release of cytochrome c from the mitochondria and activation of caspase-3 (Skorski, 2002;Slupianek et al, 2002).…”