Blood, 1 April 2001, Vol. 97, No. 7, pp. 1905-1905
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-PKCS). Down-regulation of DNA-PKCS was also detected in
CD34+ cells from CML patients. Moreover,
DNA-PKCS 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-PKCS. BCR/ABL-expressing cells with undetectable DNA-PKCS 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-PKCS deficiency is associated with defective
nonhomologous end joining (NHEJ) repair of double-strand breaks. Thus
DNA-PKCS knock-out cells exhibit pronounced
radiosensitivity, whereas DNA- PKCS knock-out mice show
increased incidence of thymic lymphoma and preneoplastic lesions in
other tissues. BCR/ABL-expressing cells with undetectable levels of
DNA-PKCS were not markedly more radiosensitive of parental
cells or BCR/ABL cells with detectable levels of DNA-PKCS.
Deutsch and colleagues suggest that the radiosensitivity induced by
DNA-PKCS 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-PKCS down-regulation in CML hematopoietic progenitors and the pathway(s) whereby BCR/ABL elicits DNA-PKCS
degradation. 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.
Bruno Calabretta
Kimmel Cancer Center
