The partial tandem duplication of ALL1 in acute myeloid leukemia with normal cytogenetics or trisomy 11 is restricted to one chromosome

The molecular defects responsible for tumorigenesis in adult de novo acute myeloid leukemia (AML) with a normal karyotype or an additional copy of one chromosome (i.e., trisomy) remain largely unknown. We recently discovered that approximately 90% of adult patients with de novo AML and trisomy 11 (+11) as a sole abnormality and 11% of adult patients with de novo AML and normal cytogenetics carry a molecular rearrangement of the All1 (MLL, HRX, or HTRX) gene. The rearranged ALL1 gene has been shown to result from the direct tandem duplication of a portion of ALL1 itself. To better understand the underlying mechanisms of leukemogenesis, we asked whether in cytogenetically normal cases one or both chromosomes carry the mutated allele and whether in trisomic cases the mutation is present in one, two, or three chromosomes. Herein we show that in cytogenetically normal cases of AML and in cases with +11 as a sole cytogenetic abnormality, only one chromosome contains the mutated ALL1 allele. Thus a single mutated ALL1 allele with the partial tandem duplication is sufficient for ALL1-associated leukemogenesis, irrespective of the number of normal genes present. The frequently occurring specific association of +11 and ALL1 gene mutation in the leukemic clone remains unexplained.