NOTCH1 point mutations, insertions, and deletions producing aberrant increases in NOTCH1 signaling are frequently present in T-cell ALL.88-90 Further, NOTCH1 signaling was shown to be required for sustained growth and, in a subset of cell lines, for survival. Finally, experiments with small-molecule inhibitors of 7-secretase, a protease required for normal NOTCH signal transduction and the activity of the mutated forms of NOTCH1, showed inhibitory activity in T-cell ALL with NOTCH1 mutations. These results provide a rationale for clinical trials with NOTCH1 inhibitors, such as 7-secretase antagonists.89'90

GENE PROFILING Relapse-classifying gene sets

Several groups have identified distinctive gene sets in diagnostic samples from patients whose disease subsequently recurred.9192 In spite of the different age groups studied (pediatric91 vs adult92), assortment of array platforms, and diverse treatment protocols, all Affymetrix ALL array data and two sets of cDNA arrays validated the predictability of these gene sets to delineate the following cytogenetic prognostic groups: hyperdiploidy, T-lineage ALL, t(12;21), t(4;11), and t(1;19).93

Resistance-classifying gene sets

A different gene profile was identified when leukemia cells were tested for in vitro sensitivity to the four most commonly used drugs in ALL, i.e., prednisolone, vin-cristine, asparaginase, and daunorubicin.94 Interestingly, only three genes for which results were significant in these analyses, RPL6, ARHA, and SLC2A14, have previously been associated with resistance to doxorubicin. Two gene expression profiles that differed according to sensitivity or resistance to the four drugs were compared with treatment outcome. These two gene sets were significantly and independently predictive of outcome. They are now being analyzed in prospective studies to tailor treatment according to patterns of resistance.

0 0

Post a comment