No abstract

It has been demonstrated that the chromosomal translocation t(7;11)(p15;p15) in patients with human acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) invariably involves fusion of the nucleoporin gene, NUP98, on chromosome 11 and the class 1 HOX gene, HOXA9, on chromosome 7, and that the fusion gene NUP98-HOXA9 is an important gene in myeloid leukemogenesis. Here are reported 2 novel chromosome 7p15 targets of the t(7;11)(p15;p15) chromosomal translocation in 2 patients with CML and myelodysplastic syndrome (MDS). Southern blot and polymerase chain reaction (PCR) analyses of leukemia cell DNA failed to show rearrangement of HOXA9, whereas NUP98 was found to be rearranged in both cases. Reverse transcription-PCR analysis using a NUP98 primer and a degenerate primer corresponding to the third helix of the homeodomain of HOXA demonstrated that NUP98 was fused in-frame to HOXA11 in the patient with CML and to HOXA13 in the patient with MDS. The chromosomal breakpoints on 7p15 were located within introns of HOXA11 or HOXA13 genes. In both patients chimeric NUP98-HOXA9 transcripts were also observed. These findings suggest that AbdB-type HOXA genes are common targets of t(7;11)(p15; p15) chromosomal translocations and that a single translocation can produce more than one NUP98-HOXA fusion gene, presumably because of altered splicing. IntroductionChromosomal translocations are frequently associated with human leukemias and sarcomas. 1 Various transcription factor genes are involved in these translocations. As a result of the gene fusion, chimeric transcription factors, which acquire novel function, are synthesized. 2 Translocations involving chromosome 11p15 have been observed in patients with human acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelogenous leukemia (CML) and in one patient with T-cell acute lymphoblastic leukemia (T-ALL), with the breakpoint commonly occurring within the nucleoporin gene, NUP98. [3][4][5][6][7][8][9][10][11][12][13][14] These translocations result in a fusion gene, consisting of NUP98 and a target gene on a number of specific chromosomes. The genes commonly identified as fused to NUP98 are homeobox genes and include PMX1 on 1q23, 3 HOXD13 on 2q31, 4 and HOXA9 on 7p15. [5][6][7][8] Numerous HOX genes have been shown to have leukemogenic potential, 15 and HOXA9 in particular appears to be important in myeloid leukemogenesis. Studies of gene expression in patients with AML suggest that the overexpression of HOXA9 is associated with poor prognosis. 16 Hoxa7 and Hoxa9 are the frequent targets of retroviral integration in the murine BXH2 myeloid leukemias. 17 Murine bone marrow transplantation experiments involving the transfer of murine hematopoietic cells overexpressing Hoxa9 induce AML after a long latency period. 18 In addition, constitutive expression of Hoxa9 immortalizes myeloid progenitors in vitro. 19 We describe here 2 novel breakpoints within the HOXA cluster on 7p15 in 2 patients with CML or MDS and the chromosomal translocat...