Adults and infants with acute leukemia and disruption of the ALL1 gene (at chromosome 11q23) are more likely to fail to respond to treatment or to suffer early relapse than the overall leukemia population. Although chromosome translocations that disrupt ALL1 can be recognized, submicroscopic rearrangements in this gene have been identified in individuals without cytogenetic rearrangements involving chromosome II. Both euploid and trisomy Il constitutions have been seen in this cohort of patients. in all cases studied to date, these mutations have resulted from an internal duplication of variable length (usually involving some or all of exons 2 through 8 of ALL1). It is not clear how often ALL1 mutations are missed in children. The primary purpose of this study is to retrospectively and prospectively identify mutations in children who do not have chromosome 11 translocations. By Southern hybridization with an ALL1 probe, we have identified one child with a rearrangement in this gene and mosaicism for trisomy 11 in the blast lineage. This approach may not be adequately detect disruption of ALL1 when it is present in a subset of blast cells. in this proposal, reverse-transcription followed by the polymerase chain reaction (PCR) will be used prospectively and long PCR assays will be used retrospectively to identify patients with ALL1 mutations. Following the identification of individuals with ALL1 mutations, we will determine whether one or more clinical parameters that characterize the leukemia are correlated with this genotype. Ultimately, the identification of cryptic ALL1 mutations in children with otherwise normal chromosome 11 constitutions may be useful in predicting how well they will respond to treatment or determining which treatment is most appropriate.
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