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.     

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.     

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.     

t(7;11)(p15;p15) Chronic myeloid leukaemia developed into blastic transformation showing a novel NUP98/HOXA11 fusion

We encountered a patient with Philadelphia-negative chronic myeloid leukaemia, with t(7;11)(p15;p15), in whom acute leukaemia phase (acute myeloid leukaemia-M2 morphology) developed within a short period. We detected a novel gene fusion between NUP98 and HOXA11 both in the chronic phase and in the acute leukaemia phase in this case. Although it is well known that a fusion of NUP98-HOXA9 in myeloid malignancies is created by the t(7;11)(p15;p15), this case suggests the possibility that HOXA11 might be another partner gene for NUP98 in t(7;11)(p15;p15) leukaemia.     

Acute myelogenous leukemia with the t(3;12)(q26;p13) translocation: case report and review of the literature

Translocations involving the EVI1/MDS1 gene at 3q26 and the TEL gene at 12p13 are comparatively common in acute leukemia, but a translocation between the two genes has been reported only in a handful of cases. We report an additional case of acute myelogenous leukemia (AML) preceded by a myelodysplastic syndrome (MDS) with the translocation t(3;12)(q26;p13) in a 36-year-old woman. The translocation was present early in the disease and long before the MDS progressed to AML 3 years after diagnosis. At the time of progression to AML, an additional chromosomal abnormality, a monosomy 22, was discovered. The patient was treated with the protocol MAQ, which comprised mitoxantrone, aracytine, and quinine, as her blasts expressed the p-glycoprotein, but she failed to obtain remission. A second treatment with the same protocol resulted in only minimal response. The patient was treated again with high-dose Ara-C and idarubicine in an attempt to achieve a response before allogeneic unrelated transplantation, but she did not respond to the treatment and died shortly thereafter. A review of the literature revealed 12 other cases of the t(3;12)(q26;p13) translocation. Characteristics of those cases are reviewed in this article.     

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.     

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.     

Hemophagocytosis by leukemic blasts in a case of acute megakaryoblastic leukemia with t(16;21)(p11;q22).

We report the case of a 2-year-3-month-old boy with acute megakaryoblastic leukemia showing hemophagocytosis by leukemic blasts. The chromosome analysis of his bone marrow revealed t(16;21)(p11;q22). In addition to the present case, we found 4 other acute myeloid leukemia (AML) cases associated with hemophagocytosis and t(16;21)(p11;q22) in the literature, of which 3 were megakaryoblastic. Although the syndrome of AML with FAB-M4/5 morphology, t(8;16)(p11;p13), and erythrophagocytosis is well known, leukemic blasts of FAB-M7 morphology showing t(16;21)(p11;q22) may be underscored for their phagocytic activity.     

Inhibition of apoptosis by BCL2 prevents leukemic transformation of a murine myelodysplastic syndrome

Programmed cell death or apoptosis is a prominent feature of low-risk myelodysplastic syndromes (MDS), although the underlying mechanism remains controversial. High-risk MDS have less apoptosis associated with increased expression of the prosurvival BCL2-related proteins. To address the mechanism and pathogenic role of apoptosis and BCL2 expression in MDS, we used a mouse model resembling human MDS, in which the fusion protein NUP98-HOXD13 (NHD13) of the chromosomal translocation t(2;11)(q31;p15) is expressed in hematopoietic cells. Hematopoietic stem and progenitor cells from 3-month-old mice had increased rates of apoptosis associated with increased cell cycling and DNA damage. Gene expression profiling of these MDS progenitors revealed a specific reduction in Bcl2. Restoration of Bcl2 expression by a BCL2 transgene blocked apoptosis of the MDS progenitors, which corrected the macrocytic anemia. Blocking apoptosis also restored cell-cycle quiescence and reduced DNA damage in the MDS progenitors. We expected that preventing apoptosis would accelerate malignant transformation to acute myeloid leukemia (AML). However, contrary to expectations, preventing apoptosis of premalignant cells abrogated transformation to AML. In contrast to the current dogma that overcoming apoptosis is an important step toward cancer, this work demonstrates that gaining a survival advantage of premalignant cells may delay or prevent leukemic progression.     

t(4;11)(q21;p15) translocation involving NUP98 and RAP1GDS1 genes: characterization of a new subset of T acute lymphoblastic leukaemia

Two cases of T acute lymphoblastic leukaemia (T-ALL) with an identical t(4;11)(q21;p15) translocation were identified within a prospective study on the biological and clinical features of adult ALL patients enrolled into the therapeutic protocol ALL0496 of the GIMEMA Italian Group. In both cases, the molecular characterization showed an involvement of the NUP98 gene on 11p15 which rearranges with the RAP1GDS1 gene on 4q21. The morphological and immunological features of the leukaemic cells, as well as the clinical behaviour and response to induction therapy, were the same in both patients. Based on the available data, the t(4;11)(q21;p15) translocation involving the NUP98-RAP1GDS1 fusion gene emerges as a new highly specific genetic abnormality that characterizes a subset of T-ALL.