MEL1 at 1p36.3 Is Fused to Several Partner Genes Including HOXA9 Located at Different Chromosomal Bands from 3q21.3 in t(1;3)(p36.3;q21.3)-Leukemia.

In MDS/AML with t(1;3)(p36;q21), overexpression of MEL1 lacking PR domain (MEL1S) driven by the RPN1 promoter at 3q21.3 is reported to be closely associated with the pathogenesis. Previously, we have defined the 1p36.3 breakpoint (BP) in 5 patients and the 3q21.3 BP in 4 patients with BAC/PAC probes. The BPs at 1p36 were clustered within 3 BP regions (BR), spanning an approximately 200-kb area: BR-1, a 70-kb region in the first intron of MEL1 covered by RP1-163G9; BR-2, a 29-kb region in 5′ region of MEL1 covered by RP5-907A6; BR-3, a 68.5-kb region between the BR-1 and BR-2. On the other hand, the BPs at 3q21.3 were clustered within only one BR, a 108.9-kb region belonging to RP11–475N22, centromeric to RPN1, in which GR6 gene and the promoter region of GATA2 gene are included. Among 5 patients, 2 had the 1p36.3 BPs within the first intron of MEL1, suggesting the existence of MEL1 fusion genes. As expected, using 3′- and 5′-RACE, we have identified 10 MEL1 fusion genes including MEL1/HOXA9 among the 4 patients, not only in patients with the 1p36.3 BP within MEL1 but also in patients with the 1p36.3 BP outside MEL1. None of reciprocal fusion transcripts were detected. Using two normal bone marrow samples and HNT-34 cell line as control, no MEL1 fusion transcripts were detected with TA cloning analysis of 50 clones obtained from each sample. Surprisingly, none of these partner genes were located at band 3q21.3, suggesting that different mechanisms from chromosome translocation might be involved in generating these fusion transcripts. This is the first report showing that MEL1 is involved in the (1;3)(p36;q21)-leukemia not only by inappropriate expression but also by generation of fusion transcripts. Taken together, our findings suggest that in addition to overexpression of MEL1S, MEL1 fusion transcripts may play important roles in the pathogenesis of t(1;3)-leukemia.