Acute myeloid leukemia (AML), probably treatment related and chronic myeloid leukemia (CML) in progression.

Acute myeloid leukemia in 4: 2 patients with AML with maturation (AML-M2), in 1 of them that developed 3 years after the start of chemotherapy (MACOP-B) for stage III non-Hodgkin lymphoma (NHL)(immunoblast type) (Nakamura et al., 1999; Hatano et al., 2000) and in the other it was diagnosed 3 years after chemotherapy (ifosfamide, adriamycin, cytoxan, etopside) and radiotherapy for sarcoma of the testis (Soares et al., 2006). 1 patient was diagnosed with AML with minimal maturation (AML-M1) who received chemotherapy (adriamycin, cytoxan, 5-FU) and bone marrow transplantation for breast adenocarcinoma (Kobzev et al., 2004), 1 with myelodysplastic syndrome evolving into acute myelomonocytic leukemia (M4) that developed after chemotherapy (doxorubicin, ifosfamide) and radiotherapy for liposarcoma with the latency period from chemotherapy to the onset of MDS (treated with azacytidine) 30 months and of AML 38 months (Zhang et al., 2007). 2 patients had CML in transformation, 1 of them on hydrea and myleran therapy (Kobzev et al., 2004) and the other received hydroxyurea during the chronic phase and chemotherapy (arabinosylcytosine, aclamycin, daunarubicin) during transformation that developed after 2.5 years of chronic phase (Bai et al., 2006). Our unpublished case received chemotherapy (MECOB-P) for B-cell NHL and developed chronic myelomonocytic leukemia (CMML) 18 month later.

5 patients with confirmed NUP98 rearrangement (4 males and 1 female aged 42 to 74 years, median 51 years) (Hatano et al., 2000 Kobzev et al., 2004; Bai et al., 2006; Zhang et al., 2007) and an 18 years old male without molecular studies (Soares et al., 2006). NUP98 rearrangement was also detected in a 36 years old male (unpublished data).

In 1 AML-M2 patient, complete remission of leukemia was achieved, but the NHL relapsed and an advanced gastric carcinoma was found and the patient died shortly afterwards (Hatano et al., 2000) and the other patient with AML-M2 died 5 months after leukemia onset (Soares et al., 2006). The 2 other AML patients died shortly after the onset of leukemia (Kobzev et al., 2004; Zhang et al., 2007) as well as the patient with CML in transformation (Kobzev et al., 2004). From these data it appears that the clinical course of patients is quite aggressive and the prognosis is dismal.

Patients had variable breakpoints assigned to chromosome 1q, but FISH and/or molecular studies confirmed the involvement of PRRX1 that is mapped to 1q24.2, therefore chromosome 1 breakpoints in patients were the same.

Sole anomaly in 1 AML (Kobzev et al., 2004) and in 1 patient during the MDS phase (Zhang et al., 2007); found in association with limited anomalies in the remaining AML patients: +8 (Zhang et al., 2007) and del(7q)/+8 subsequently acquired during MDS progression (Zhang et al., 2007). Sole additional anomaly to t(9;22)(q34;q11) in both progressed CML patients (Kobzev et al., 2004; Bai et al., 2006); found as the only karyotypic anomaly in our unpublished case.

5-NUP98/PRRX1-3. In frame fusion of NUP98 exon 12 to PRRX1 exon 2; no reciprocal fusion transcript.The juxtaposition of the part of the DNA-binding homeodomain of PRRX1 to the N-terminal GLFG repeats of NUP98 leads to the generation of leukemogenic NUP98/PRRX1 fusion protein; the PRRX1 homeodomain may be upregulated.

Chromosomal translocations of the nucleoporin NUP98 gene have been described in de novo and therapy-related hematopoietic malignancies, in particular acute myeloid leukemia. The formation of chromosomal rearrangements that generate NUP98 fusion proteins suggests that aberrant expression of NUP98 fusion proteins may be a causal event for leukemic transformation. In all of the leukemia-associated NUP98 fusions described thus far, the FG repeats of NUP98 are always retained, thus they are capable of interacting with HDAC1 and CREBBP that may enable them to act as both trans-activators and trans-repressors. (Bai et al., 2006). NUP98/PRRX1 generated by t(1;11)(q24.2;p15.4) shares these features with other NUP98 chimeric proteins, suggesting that the FG repeats on its N-terminus possess a critical role in leukemic transformation. Notably, all described patients with this rearrangement had a history of malignant tumor and leukemia developed after chemotherapy with topoisomerase II inhibitors and alkylating agents. Therefore, it is likely that the NUP98 locus is vulnerable to genotoxic induced chromosomal rearrangements.

NUP98/PRRX1 NUP98 (11p15.4) PRRX1 (1q24.2) M t(1;11)(q24;p15)|NUP98/PRRX1 NUP98 (11p15.4) PRRX1 (1q24.2) TIC

Included are patients with 1q21-25 breakpoints and confirmed NUP98 rearrangement.