ACUTE LEUKEMIAS OF DIFFERENT LINEAGES HAVE SIMILAR MLL GENE FUSIONS ENCODING RELATED CHIMERIC PROTEINS RESULTING FROM CHROMOSOMAL TRANSLOCATION

The MLL gene, on human chromosome 11q23, undergoes chromosomal translo cation in acute leukemias, resulting in gene fusion with AF4 (chromoso me 4) and ENL (chromosome 19). We report here translocation of MLL wit h nine different chromosomes and two paracentric chromosome 11 deletio ns in early B cell, B- or T-cell lineage, or nonlymphocytic acute leuk emias. The mRNA translocation junction from 22 t(4;11) patients, inclu ding six adult leukemias, and nine t(11;19) tumors reveals a remarkabl e conservation of breakpoints within MLL, AF4, or ENL genes, irrespect ive of tumor phenotype. Typically, the breakpoints are upstream of the zinc-finger region of MLL, and deletion of this region can accompany translocation, supporting the der(11) chromosome as the important comp onent in leukemogenesis. Partial sequence of a fusion between MLL and the AFX1 gene from chromosome X shows the latter to be rich in Ser/Pro codons, like the ENL mRNA. These data suggest that the heterogeneous 11q23 abnormalities might cause attachment of Ser/Pro-rich segments to the NH2 terminus of MLL, lacking the zinc-finger region, and that tra nslocations occur in early hematopoietic cells, before commitment to d istinct lineages.