INFANT ACUTE LEUKEMIAS SHOW THE SAME BIASED DISTRIBUTION OF ALL1 GENEBREAKS AS TOPOISOMERASE-II RELATED SECONDARY ACUTE LEUKEMIAS

The ALL1 gene (also called MLL, HRX, or Htrx1) at the cytogenetic band 11q23 is consistently altered by chromosome rearrangements in acute l eukemias (ALs) of early infancy, in ALs developed after exposure to to poisomerase (topo) II-inhibitory drugs, and in a small subset of de no vo ALs in children and adults, Because exposure to natural or medicina l substances blocking topo II during pregnancy have been proposed as e tiological agents for infant leukemia, we have compared the distributi on of ALL1 gene breakpoints in infant leukemias with an altered ALL1 g ene configuration to those in secondary leukemia associated with prior exposure to topo II targeting drugs and in reference to the major top o consensus binding site in exon 9, ALL1 gene breakpoint distribution was determined by Southern blot hybridization and/or reverse transcrip tion-PCR of the ALL1/AF4 fusion cDNA in 70 patients, Using restriction enzyme analysis, the 8.3-kb ALL1 breakpoint cluster region was divide d in a centromeric portion of 3.5 kb (region A) and telomeric portion of a 4.8 kb (region B), ALL1 breakpoint were located in region A in 8 of 28 (28.5%) cases of infant ALs, 16 of 24 (66%) cases of de novo ALs , and 0 of 5 cases of therapy-related (TR) ALs, Conversely, ALL1 break points in region B were detected in 20 of 28 (71.5%) cases of infant A L, 8 of 24 (33%) cases of de novo AL, and 5 of 5 (100%) cases of TR AL (P = 0.002), These results were confirmed by direct sequencing of the ALL1/AF4 fusion transcript in 30 cases (19 infants and 11 child and a dult de novo cases), The analysis of ALL1/AF4 junction types showed th at children and adults with de novo leukemia had ALL1 breakpoints in i ntron 6 (9 cases) or intron 7 (2 cases), whereas breakpoints in infant cases were mainly located in intron 8 (14 cases) and less frequently in intron 6 (4 cases) and intron 7 (1 case), The difference in ALL1 br eakpoint location between infant and noninfant AL patients with ALL1/A F4 fusion was statistically significant (P = 0.00005). These data demo nstrated that infant and TR ALs share a similar biased clustering of A LL1 gene breakpoints, which supports the possibility that topo II inhi bitors may also operate in utero and play a crucial role in the etiolo gy of infant leukemia.