Duplication or amplification of chromosome band 11q23, including the unrearranged MLL gene, is a recurrent abnormality in therapy-related MDS and AML, and is closely related to mutation of the TP53 gene and to previous therapy with alkylating agents

Gene amplification is a rare phenomenon in acute leukemia, but recently amp lification of specific chromosome bands containing genes rearranged in leuk emia-specific balanced chromosome translocations has been reported in a few cases. We detected duplication or amplification of chromosome band 11q23 w ith 3-7 copies of the MLL gene by fluorescence in situ hybridization in 12 out of 70 unselected patients with therapy-related myelodysplasia or acute myeloid leukemia (17%). In all but one case, the supernumerary copies of ML L were located to previously unidentified marker chromosomes or unbalanced translocations. In 4 of the 12 patients, 2-6 copies were located together o n the same chromosome arm representing amplification, 7 patients had single , extra duplicated copies of MLL, whereas both amplification and duplicatio n were observed in the same cell in I patient. Comparative genomic hybridiz ation demonstrated gain of varying, often large parts of I Iq in five patie nts. The MLL gene was shown to be unrearranged in all 12 patients. Seven ou t of eight patients with duplication or amplification of MLL had mutations of TP53. Patients with supernumerary copies of MLL were in general older (P = 0.007) and had a shorter survival (P < 0.001) compared to other patients . Duplication or amplification of MLL was significantly associated with a c omplex karyotype (P = 0.002), with deletion or loss of 5q (P = 0.001), and with prior therapy with alkylating agents. These results support the existe nce of a specific genetic pathway in t-MDS and t-AML with many previously u nidentified chromosome aberrations demonstrated to represent extra copies o f parts of I Iq, including the unrearranged MLL gene. <(c)> 2001 Wiley-Liss , Inc.