Comment on Holleman et al, page 769
Holleman and colleagues report finding differential expression of groups of apoptotic genes with differing subgroups of ALL, but only one such gene associated significantly with drug resistance and risk of relapse—BCL2L13 (Bcl-rambo).
Apoptosis, mitochondrial or death-receptor mediated, is one of the main mechanisms of tumor cell death induced by chemotherapeutic agents. Cellular drug resistance has been linked with unfavorable prognosis in leukemia,1 and with a decreased ability to induce apoptosis. To date, few genes have been examined as potential mediators of drug resistance through apoptosis. In this issue of the journal, Holleman and colleagues report the results of their extensive evaluation of 70 apoptosis genes in this regard.
The authors studied children treated both in Holland and in the United States (St Jude) for acute lymphoblastic leukemia (ALL). This work is the first to describe an association between differential apoptotic gene expression and leukemia lineage, genetic subtype, and in vitro drug resistance in childhood ALL. Although only one of these genes was found to associate independently with patient outcome, it is of considerable interest.
This gene, BCL2L13, was also found to be significantly related to resistance to one drug, l-asparaginase. The clinical significance of this is the potential for down-regulation of this gene by antisense oligonucleotides or specific inhibitor therapy. This approach could sensitize the ALL cells to l-asparaginase.
This is exciting news, but must be tempered a bit. First, the number of patients studied was relatively small (190 from Holland, 92 from St Jude). Second, this was a retrospective study and would need to be validated in a prospective manner. Third, the authors did not have enough patients with T-lineage ALL to study it meaningfully. This is unfortunate, since this is a large subgroup of pediatric ALL and is one of the most difficult to treat. And last, some of the analyses for risk of relapse involved very small patient numbers (eg, < 10 each for BCR-ABL, E2A-rearranged, or MLL-rearranged cases).
Of interest, the association of this gene's expression and outcome was counterintuitive. Increased messenger RNA levels of this gene were associated with cellular resistance to l-asparaginase and an increase relapse rate. Based on cell line work, one would have expected an increased expression of this proapoptotic gene to have led to an increase in cell kill and hence fewer relapses. One explanation offered by the authors is posttranslational production of splice variants that have relatively more antiapoptotic function. Protein expression and function studies will need to be conducted to sort this out.
We look forward to others duplicating this work, in prospective studies. If the finding of Holleman et al is confirmed, it could lead to significant clinical improvement in outcome, since l-asparaginase is very important to long-term outcome for many children with ALL.2,3 ▪
