Defective DNA repair in CML

The transition of chronic myelogenous leukemia (CML) from chronic phase to blast crisis is marked by the accumulation of a variety of genetic abnormalities that underlie the rapidly fatal progression of CML-blast crisis. Although this transition cannot yet be investigated in CML mouse models, it is believed that the antiapoptotic effects exerted by the BCR/ABL oncoprotein may favor the emergence of cell clones carrying additional genetic abnormalities.

In this issue, Deutsch and colleagues (page 2084) provide evidence for a potentially important novel mechanism that may involve defective DNA repair. Stable and conditional BCR/ABL expression in hematopoietic cells was associated with down-regulation of the catalytic subunit of the DNA-dependent protein kinase (DNA-PK_CS). Down-regulation of DNA-PK_CS was also detected in CD34⁺ cells from CML patients. Moreover, DNA-PK_CS expression was restored by tyrosine kinase and proteasome inhibitors, suggesting that BCR/ABL tyrosine kinase activates a pathway(s) leading to proteasome-dependent degradation of DNA-PK_CS. BCR/ABL-expressing cells with undetectable DNA-PK_CS levels exhibited a high frequency of chromosomal aberrations upon exposure to ionizing radiation (IR). IR-induced chromosomal aberrations were markedly reduced in cells incubated with a tyrosine kinase inhibitor.

DNA-PK_CS deficiency is associated with defective nonhomologous end joining (NHEJ) repair of double-strand breaks. Thus DNA-PK_CS knock-out cells exhibit pronounced radiosensitivity, whereas DNA- PK_CS knock-out mice show increased incidence of thymic lymphoma and preneoplastic lesions in other tissues. BCR/ABL-expressing cells with undetectable levels of DNA-PK_CS were not markedly more radiosensitive of parental cells or BCR/ABL cells with detectable levels of DNA-PK_CS. Deutsch and colleagues suggest that the radiosensitivity induced by DNA-PK_CS down-regulation might be counterbalanced by enhanced resistance of BCR/ABL-expressing cells to IR-induced apoptosis. Possibly, the concomitant deficiency in NHEJ repair of double-strand breaks and enhanced resistance to apoptosis by IR or radiomimetic drugs favor the accumulation of genetic abnormalities during CML disease progression.

This study raises interesting questions regarding the frequency of DNA-PK_CS down-regulation in CML hematopoietic progenitors and the pathway(s) whereby BCR/ABL elicits DNA-PK_CSdegradation. It also raises the question of whether BCR/ABL affects the expression of DNA-PK regulatory subunits and whether other repair mechanisms are also perturbed in BCR/ABL-expressing cells. Finally, the availability of several mouse lines with various types of DNA-PK deficiency may provide useful models in which to test whether DNA-PK deficiency accelerates BCR/ABL-dependent leukemogenesis.