SET-NUP214 rearrangement in isolation is insufficient to induce leukemia: a single center experience

SET-NUP214 rearrangement was first reported in 1990 with increasing strong association with T-cell acute lymphoblastic leukemia (T-ALL). Recently, it was reported that this specific rearrangement in isolation was not leukomegenic [1,2]. Herein, we report two cases of acute leukemia with SET-NUP214 rearrangement and complex karyotype. To characterize the SET-NUP214 rearrangement, 41 adult ALL patients were screened using HemaVision kit (DNA Technology, Risskov, Denmark) and two were found SETNUP214 positive with frequency of 4.9%, which is equal to a previous study [2]. The first patient, a female, 48-years old, was admitted to the hospital due to general lymphadenopathy. Her blood count indicated anemia and leukopenia and film examination showed 59% large size blasts. Bone marrow biopsy and biopsy from the cervical node were performed. The diagnosis of early T ALL was made (CD7, CD5 dim, sCD3-, cCD3, CD4-, CD8-, CD34, HLADR, CD117, MPO). Cytogenetic analysis showed a complex karyotype including deletion of chromosomes 12, 13, 17 and 18. The second patient, a male, 45-years old, was admitted to the hospital due to easy tiredness and bone pain. His blood count showed lymphocytosis and film examination revealed 63% large blasts. His bone marrow aspiration was a dry tap. His computed tomography scan revealed generalise lymphadenopathy. Both bone marrow biopsy and immunophenotypic analysis of peripheral blood (CD7, CD38, CD34, CD3, CD42, CD82, CD33, CD1a2) put the diagnosis of early T-ALL. In both cases, a single SET-NUP214 transcript was amplified by RT-PCR and sequencing of the fusion transcript revealed fusion of the exon 7 of SET to exon 18 through exon 32 of NUP214 (Figure 1a). This fusion transcript is identical to that described in the previously published cases [3,4]. The rare rearrangement was further investigated with array-CGH analysis. Both patients shared del (17)(q11.2), del(6)(q16.1-q21) and del(12)(p12.1-13.1) – spanning the ETV6 and CDKN1B gene loci – that have also been described in other published cases with SETNUP2142 (Figure 1b). The female patient received combination chemotherapy followed by allogeneic stem cell transplantation from her fully matched sibling. After 1 year her disease relapsed and she died during reinduction therapy. The male patient also received combination chemotherapy followed by allogeneic stem cell transplantation from a fully matched unrelated donor. He died 6 months after the transplantation. SET-NUP rearrangement produces a fusion protein that inhibits the cell apoptosis caused by the cytotoxic T-cells. It has recently been reported to have an association with T-acute lymphoblastic leukemia and acute undifferentiated leukemia and rarely with acute myelogenous leukemia. The fusion gene also inhibits the differentiation. However, it is proved, in mice, that the co-existence with other gene abnormalities is necessary for the development of leukemia. In a study, SET-NUP214 was found, along with over-expression of HOXA7, HOXA9 and HOXA10 in two among 256 patients with ALL [5]. Wang et al. [6] detected co-existence with PHF mutations in three among 46 ALL patients. Van Vlierberghe et al. [4] have reported the possible contribution of NOTCH14 in ALL patients with SET-NUP214. Gorello et al. [2] mentioned the poor prognosis of patients with SET-NUP214 combined with complex karyotype. The reported cases are still too few to draw inferences. In conclusion, SET-NUP214 rearrangement is insufficient to induce leukemia by itself, therefore it needs additional chromosomal aberrations to induce leukemogenesis. It seems that the complex karyotype and possibly the ETV6 and CDKN1B deletions detected in the many cases with SET-NUP214 are critical to the phenotype and to prognosis of this type of acute leukemia. Leukemia & Lymphoma, February 2016; 57(2): 451–452