SET domain and mariner transposase fusion gene (SETMAR), also known as Metnase, has previously been shown to suppress the formation of chromosomal translocation in mouse fibroblasts. Despite the fact that hematologic malignancies are often characterized by chromosomal rearrangements, no studies have hitherto investigated the expression pattern of the gene in these disorders. We hypothesized that a high expression of SETMAR protected the cells from chromosomal rearrangements; thus, we examined the mRNA expression of SETMAR transcript variants in hematologic patients. We identified six transcript variants (var1, var2, var5, varA, varB, varC), of which three had not been reported previously. Expression levels were quantified by transcript-specific quantitative polymerase chain reaction in 15 healthy individuals, 70 acute myeloid leukemia (AML) patients (translocation positive, n= 30 [AMLTPos], translocation negative, n = 40 [AMLTNeg]), seven patients with mantle cell lymphoma (t [11,14] positive), and 13 patients with chronic myeloid leukemia (t [9,22] positive). All variants were significantly overexpressed in both subgroups of AML compared with healthy individuals (var1 and var2: p < 0.00001 for both AML subgroups, varA and varB: p = 0.0002, var5: p = 0.0008, and varC: p = 0.0001 for AMLTNeg; varA: p = 0.0048, varB and var5: p = 0.0001, varC: p = 0.0017). When comparing the expression in AMLTNeg and AMLTPos, we found a significantly increased expression of the full length SETMAR in AMLTNeg (var1: p = 0.047), suggesting a protective effect of high SETMAR expression on formation of chromosomal translocations. In conclusion, we have found known and novel SETMAR splice variants to be significantly increased in AML. To our knowledge, this is the first study that describes an expression profile of SETMAR in subgroups of hematologic malignancies, which can be linked to the incidence of chromosomal rearrangements.