The t(11;20)(p15;q11) chromosomal translocation associated with therapy-related myelodysplastic syndrome results in an NUP98-TOP1 fusion.

The NUP98 gene is involved in 3 distinct chromosomal rearrangements, t(7;11)(p15;p15), t(2;11)(q31;p15), and inv(11)(p15q22); all of these NUP98 rearrangements have been identified in the malignant cells of patients with therapy-related acute myelogenous leukemia or myelodysplastic syndrome (t-AML/MDS). Here we report the cloning and characterization of a t(11;20)(p15;q11) translocation from patients with t-MDS. The breakpoint on chromosome 11p15 targets the NUP98 gene and results in the separation of the N-terminal FXFG repeats from the RNA-binding domain located in the C-terminus. The breakpoint on chromosome 20q11 occurs within the gene encoding human DNA topoisomerase I (TOP1). As a result, a chimeric mRNA encoding the NUP98 FXFG repeats fused to the body of DNA topoisomerase I is produced. These results indicate that NUP98 is a recurrent target in therapy-related malignancies, and that TOP1 is a previously unrecognized target for chromosomal translocations.     

Additional acquisition of t(1;21)(p32;q22) in a patient relapsing with acute myelogenous leukemia with NUP98-HOXA9

We report a 29-year-old Japanese male with acute myelogenous leukemia (AML)-M4 with a cryptic t(7;11)(p15;p15), in which a chimeric NUP98-HOXA9 fusion was detected by polymerase chain reaction analysis and a chromosomal analysis showed 46,XY. The patient received intensive chemotherapy and underwent autologous stem cell transplantation, and remission was confirmed by the disappearance of NUP98-HOXA9. However, 6 months after transplantation, the patient relapsed; NUP98-HOXA9 was detected again and karyotypic analysis revealed 46,XY, t(1;21)(p32;q22). Fluorescent in situ hybridization (FISH) analysis using an AML1-ETO translocation dual probe, showed that the 21q22 breakpoint involved AML1 locus. A retrospective FISH analysis showed that t(1;21) was absent at onset. This is the first reported case with AML who had a cryptic t(7;11)(p15;p15), and additionally acquired t(1;21)(p32;q22) at relapse.     

Involvement of the NUP98 Gene in a Chromosomal Translocation t(11;20)(p15;q11.2) in a Patient With Acute Monocytic Leukemia (FAB-M5b)

We report here a case of acute monocytic leukemia (M5b subtype according to the French-American-British [FAB] classification) with chromosomal translocation t(11;20)(p15;q11.2). Fluorescence in situ hybridization analysis with a probe for the NUP98 gene, which is located at chromosome band 11p15, showed that the probe hybridized to both derivative chromosomes 11 and 20 as well as to the remaining normal chromosome 11, indicating that the NUP98 gene was split and involved in this translocation. This is the first report of t(11;20)(p15;q11.2) involving the NUP98 gene in overt leukemia.     

Human homologue of the rat chondroitin sulfate proteoglycan, NG2, detected by monoclonal antibody 7.1, identifies childhood acute lymphoblastic leukemias with t(4;11)(q21;q23) or t(11;19)(q23;p13) and MLL gene rearrangements

Monoclonal antibody 7.1, which recognizes the chondroitin sulfate proteoglycan molecule NG2, was used to screen prospectively blast cells from 104 consecutive children at initial presentation with acute lymphoblastic leukemia (ALL). Reactivity with this antibody was found in 9 cases (8.6%), of whom 5 had a t(4;11)(q21;q23) and 4 had a t(11;19)(p13;q23). None of the NG2- cases had either translocation. Southern blot analysis disclosed MLL gene rearrangement in only the 9 cases with 7.1 reactivity plus the t(4;11)(q21;q23) or t(11;19)(q23;p13) translocation. MLL gene rearrangements were not detected in 89 patient leukemic samples that did not express NG2, including 7 patients with del(11)(q23) or inv(11)(p13q23). As expected from the association with t(4;11) and t(11;19), NG2+ cases were significantly more likely to be infants, to have hyperleukocytosis and central nervous system involvement, to be CD10-, and to express myeloid- associated antigens CD15 and CD65. Despite short follow-up duration, 3 of the NG2+ cases have relapsed while the other 101 patients remain in remission. Thus, blast cell surface expression of NG2 is useful for identifying patients with ALL having t(4;11) or t(11;19) translocations that are associated with poor prognosis, especially in the infant age group.     

A novel translocation t(1;7)(p36;q34) in three patients with acute myeloid leukaemia

Studies of large numbers of patients have enabled the identification of relatively infrequent chromosome changes, such as inv(3)(q21;q26), t(6;9)(p23;q34) and t(8;16)(p11;p11), whose clinico-biological significance is gradually becoming clearer. Translocations involving chromosomes 1 and 7 are relatively rare in myeloid neoplasias, being found in far less than 1% of cases; the rearrangement that occurs most frequently consists of an unbalanced translocation [t(1;7)(p11; p11)], resulting in complete loss of 7q, associated with therapy-related or environmentally-induced high-risk myelodysplasia. We recently observed three cases of acute myeloid leukaemia (AML) with a previously unreported balanced translocation t(1;7) (p36;q34). Case 1 underwent autologous bone marrow transplantation and remains alive in CR; cases 2 and 3 relapsed after 10 and 4 months, respectively. The response to chemotherapy observed in our cases suggests that variable clinical features might be present in the broad cytogenetic category usually referred to as '7q abnormalities' and contributes to an interesting previous observation of prolonged disease-free survival in a subset of AMLs with 7q- as the isolated chromosome change.     

Juvenile myelomonocytic leukemia with t(7;11)(p15;p15) and NUP98‐HOXA11 fusion

The t(7;11)(p15;p15) translocation has been reported as a rare and recurrent chromosomal abnormality in acute myeloid leukemia (AML) patients. The NUP98‐HOXA9 fusion gene with t(7;11)(p15;p15) was identified and revealed to be essential for leukemogenesis and myeloproliferative disease. To date, t(7;11)(p15;p15) with NUP98‐HOXA11 fusion has been reported only in one case of ph‐negative chronic myeloid leukemia (CML). Here, we report a case of a 3‐year‐old girl with juvenile myelomonocytic leukemia (JMML) carrying t(7;11)(p15;p15) abnormality with NUP98‐HOXA11 fusion. AML chemotherapy followed by bone marrow transplantation (BMT) was found to be effective in treating this disorder, and she remains in complete remission for 3 years after BMT. We suggest the possibility that AML chemotherapy might be effective for treating JMML with t(7;11)(p15;p15) abnormality and NUP98‐HOXA11 fusion. Am. J. Hematol. 2009. © 2009 Wiley‐Liss, Inc.     

NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15)

Fusion between the NUP98 and NSD3 genes in a patient with acute myeloid leukemia associated with t(8;11)(p11.2;p15), is reported for the first time. The t(8;11)(p11.2;p15) was identified by classical cytogenetics. Fluorescence in situ hybridization (FISH) analysis revealed a split signal with a mix of BAC 118H17 and 290A12, indicating the translocation disrupted NUP98. FISH restriction at 8p11-12 showed a split of BAC 350N15. Molecular investigations into candidate genes in this BAC showed the NUP98 fusion partner at 8p11.2 was the NSD3 gene. To date the NSD3 gene has never been implicated in hematologic malignancies.