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Takuro Nakamura - One of the best experts on this subject based on the ideXlab platform.
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NUP98 fusion in human leukemia dysregulation of the nuclear pore and homeodomain proteins
International Journal of Hematology, 2005Co-Authors: Takuro NakamuraAbstract:NUP98 is fused to a variety of partner genes, including abdominal B-likeHOX, in human myeloid and T-cell malignancies via chromosomal translocation involving 11p15.NUP98 encodes a 98-kd nucleoporin that is a component of the nuclear pore complex and functions in nucleocytoplasmic transport, with its N-terminal GLFG repeats used as a docking site for karyopherins. Disruption of NUP98 may affect the nuclear pore function, and the abnormal expression and altered function of fusion partners may also be critical for leukemia development. Recent studies using mouse models expressingNUP98-HOX have confirmed its leukemogenic potential, and cooperative genes forNUP98-HOXA9 in leukemogenesis have been identified in these studies. Thus, the NUP98 chimera is a unique molecule that provides valuable information regarding nuclear pore function and the role of the homeobox protein in leukemogenesis/carcinogenesis.
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single translocation and double chimeric transcripts detection of NUP98 hoxa9 in myeloid leukemias with hoxa11 or hoxa13 breaks of the chromosomal translocation t 7 11 p15 p15
Blood, 2002Co-Authors: Takashi Fujino, Kazuma Ohyashiki, A Suzuki, Yoshikazu Ito, Yoshiaki Hatano, Ikuo Miura, Takuro NakamuraAbstract:It has been demonstrated that the chromosomal translocation t(7;11)(p15;p15) in patients with human acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) invariably involves fusion of the nucleoporin gene, NUP98 , on chromosome 11 and the class 1 HOX gene, HOXA9 , on chromosome 7, and that the fusion gene NUP98 - HOXA9 is an important gene in myeloid leukemogenesis. Here are reported 2 novel chromosome 7p15 targets of the t(7;11)(p15;p15) chromosomal translocation in 2 patients with CML and myelodysplastic syndrome (MDS). Southern blot and polymerase chain reaction (PCR) analyses of leukemia cell DNA failed to show rearrangement of HOXA9, whereas NUP98 was found to be rearranged in both cases. Reverse transcription-PCR analysis using a NUP98 primer and a degenerate primer corresponding to the third helix of the homeodomain of HOXA demonstrated that NUP98 was fused in-frame to HOXA11 in the patient with CML and to HOXA13 in the patient with MDS. The chromosomal breakpoints on 7p15 were located within introns of HOXA11 or HOXA13 genes. In both patients chimeric NUP98-HOXA9 transcripts were also observed. These findings suggest that AbdB-type HOXA genes are common targets of t(7;11)(p15;p15) chromosomal translocations and that a single translocation can produce more than one NUP98 - HOXA fusion gene, presumably because of altered splicing.
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single translocation and double chimeric transcripts detection of NUP98 hoxa9 in myeloid leukemias withhoxa11 or hoxa13 breaks of the chromosomal translocation t 7 11 p15 p15
Blood, 2002Co-Authors: Takashi Fujino, Kazuma Ohyashiki, A Suzuki, Yoshikazu Ito, Yoshiaki Hatano, Ikuo Miura, Takuro NakamuraAbstract:It has been demonstrated that the chromosomal translocation t(7;11)(p15;p15) in patients with human acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) invariably involves fusion of the nucleoporin gene, NUP98, on chromosome 11 and the class 1 HOX gene, HOXA9, on chromosome 7, and that the fusion gene NUP98-HOXA9 is an important gene in myeloid leukemogenesis. Here are reported 2 novel chromosome 7p15 targets of the t(7;11)(p15;p15) chromosomal translocation in 2 patients with CML and myelodysplastic syndrome (MDS). Southern blot and polymerase chain reaction (PCR) analyses of leukemia cell DNA failed to show rearrangement of HOXA9,whereas NUP98 was found to be rearranged in both cases. Reverse transcription-PCR analysis using a NUP98 primer and a degenerate primer corresponding to the third helix of the homeodomain of HOXA demonstrated that NUP98 was fused in-frame to HOXA11 in the patient with CML and toHOXA13 in the patient with MDS. The chromosomal breakpoints on 7p15 were located within introns of HOXA11 orHOXA13 genes. In both patients chimericNUP98-HOXA9 transcripts were also observed. These findings suggest that AbdB-type HOXA genes are common targets of t(7;11)(p15;p15) chromosomal translocations and that a single translocation can produce more than oneNUP98-HOXA fusion gene, presumably because of altered splicing.
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NUP98 hoxa9 expression in hemopoietic stem cells induces chronic and acute myeloid leukemias in mice
The EMBO Journal, 2001Co-Authors: Evert Kroon, Takuro Nakamura, Guy Sauvageau, Unnur Thorsteinsdottir, Nadine MayotteAbstract:Here we describe hemopoietic chimeras serving as a mouse model for NUP98-HOXA9-induced leukemia, which reproduced several of the phenotypes observed in human disease. Mice transplanted with bone marrow cells expressing NUP98-HOXA9 through retroviral transduction acquire a myeloproliferative disease (MPD) and eventually succumb to acute myeloid leukemia (AML). The NUP98 portion of the fusion protein was shown to be responsible for transforming a clinically silent pre-leukemic phase observed for Hoxa9 into a chronic, stem cell-derived MPD. The co-expression of NUP98-HOXA9 and Meis1 accelerated the transformation of MPD to AML, identifying a genetic interaction previously observed for Hoxa9 and Meis1. Our findings demonstrate the presence of overlapping yet distinct molecular mechanisms for MPD versus AML, illustrating the complexity of leukemic transformation.
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NUP98 Is Fused to PMX1 Homeobox Gene in Human Acute Myelogenous Leukemia With Chromosome Translocation t(1;11)(q23;p15)
Blood, 1999Co-Authors: Takuro Nakamura, Yoshiaki Hatano, Yukari Yamazaki, Ikuo MiuraAbstract:The nucleoporin gene NUP98 was found fused to the HOXA9 , HOXD13 , or DDX10 genes in human acute myelogenous leukemia (AML) with chromosome translocations t(7;11)(p15;p15), t(2;11)(q35;p15), or inv(11)(p15;q22), respectively. We report here the fusion between the NUP98 gene and another homeobox gene PMX1 in a case of human AML with a t(1;11)(q23;p15) translocation. The chimeric NUP98-PMX1 transcript was detected; however, there was no reciprocal PMX1-NUP98 fusion transcript. Like the NUP98-HOXA9 fusion, NUP98 and PMX1 were fused in frame and the N-terminal GLFG-rich docking region of the NUP98 and the PMX1 homeodomain were conserved in the NUP98-PMX1 fusion, suggesting that PMX1 homeodomain expression is upregulated and that the fusion protein may act as an oncogenic transcription factor. The fusion to NUP98 results in the addition of the strong transcriptional activation domain located in the N-terminal region of NUP98 to PMX1. These findings suggest that constitutive expression and alteration of the transcriptional activity of the PMX1 homeodomain protein may be critical for myeloid leukemogenesis.
Peter D Aplan - One of the best experts on this subject based on the ideXlab platform.
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Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion
'Springer Science and Business Media LLC', 2020Co-Authors: Yi Zhang, Sheryl M Gough, Peter D Aplan, Ling Cai, Yiran Guo, Jinyong Zhang, Kendra R. Vann, Xiaobing Shi, Gang Greg WangAbstract:Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of AML. Here, the authors report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and provide evidence of a direct link between the association of NUP98-PHD finger chimeras with H3K4me3-rich regions and leukemic transformation
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effect of flt3 ligand on survival and disease phenotype in murine models harboring a flt3 internal tandem duplication mutation
Comparative Medicine, 2013Co-Authors: Emily Bailey, Peter D Aplan, Amy S Duffield, Sarah Greenblatt, Donald SmallAbstract:Many of the mutations contributing to leukemogenesis in acute myeloid leukemia have been identified. A common activating mutation is an internal tandem duplication (ITD) mutation in the FLT3 gene that is found in approximately 25% of patients and confers a poor prognosis. FLT3 inhibitors have been developed and have some efficacy, but patients often relapse. Levels of FLT3 ligand (FL) are significantly elevated in patients during chemotherapy and may be an important component contributing to relapse. We used a mouse model to investigate the possible effect of FL expression on leukemogenesis involving FLT3-ITD mutations in an in vivo system. FLT3ITD/ITD FL−/− (knockout) mice had a statistically significant increase in survival compared with FLT3ITD/ITD FL+/+ (wildtype) mice, most of which developed a fatal myeloproliferative neoplasm. These findings suggest that FL levels may have prognostic significance in human patients. We also studied the effect of FL expression on survival in a FLT3-ITD NUP98–HOX13 (NHD13) fusion mouse model. These mice develop an aggressive leukemia with short latency. We asked whether FL expression played a similar role in this context. The NUP98-HOX13 FLT3ITD/wt FL−/− mice did not have a survival advantage, compared with NUP98-HOX13 FLT3ITD/wt FL+/+ mice (normal FL levels). The loss of the survival advantage of the FL knockout group in the NUP98–HOX13 model suggests that adding a second mutation changes the effect of FL expression in the context of more aggressive disease.
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NUP98 gene fusions and hematopoietic malignancies: Common themes and new biologic insights
Blood, 2011Co-Authors: Sheryl M Gough, Christopher Slape, Peter D AplanAbstract:Structural chromosomal rearrangements of the Nucleoporin 98 gene (NUP98), primarily balanced translocations and inversions, are associated with a wide array of hematopoietic malignancies. NUP98 is known to be fused to at least 28 different partner genes in patients with hematopoietic malignancies, including acute myeloid leukemia, chronic myeloid leukemia in blast crisis, myelodysplastic syndrome, acute lymphoblastic leukemia, and bilineage/biphenotypic leukemia. NUP98 gene fusions typically encode a fusion protein that retains the amino terminus of NUP98; in this context, it is important to note that several recent studies have demonstrated that the amino-terminal portion of NUP98 exhibits transcription activation potential. Approximately half of the NUP98 fusion partners encode homeodomain proteins, and at least 5 NUP98 fusions involve known histone-modifying genes. Several of the NUP98 fusions, including NUP98-homeobox (HOX)A9, NUP98-HOXD13, and NUP98-JARID1A, have been used to generate animal models of both lymphoid and myeloid malignancy; these models typically up-regulate HOXA cluster genes, including HOXA5, HOXA7, HOXA9, and HOXA10. In addition, several of the NUP98 fusion proteins have been shown to inhibit differentiation of hematopoietic precursors and to increase self-renewal of hematopoietic stem or progenitor cells, providing a potential mechanism for malignant transformation.
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NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia
Blood, 2005Co-Authors: Ying Wei Lin, Christopher Slape, Zhenhua Zhang, Peter D AplanAbstract:The myelodysplastic syndromes (MDSs) are a group of clonal hematopoietic stem-cell disorders characterized by ineffective hematopoiesis and dysplasia. A wide spectrum of genetic aberrations has been associated with MDS, including chromosomal translocations involving the NUP98 gene. Using a NUP98-HOXD13 fusion gene, we have developed a mouse model that faithfully recapitulates all of the key features of MDS, including peripheral blood cytopenias, bone marrow dysplasia, and apoptosis, and transformation to acute leukemia. The MDS that develops in NUP98-HOXD13 transgenic mice is uniformly fatal. Within 14 months, all of the mice died of either leukemic transformation or severe anemia and leucopenia as a result of progressive MDS. The NUP98-HOXD13 fusion gene inhibits megakaryocytic differentiation and increases apoptosis in the bone marrow, suggesting a mechanism leading to ineffective hematopoiesis in the presence of a hypercellular bone marrow. These mice provide an accurate preclinical model that can be used for the evaluation of MDS therapy and biology.
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The role of NUP98 gene fusions in hematologic malignancy
Leukemia & Lymphoma, 2004Co-Authors: Christopher Slape, Peter D AplanAbstract:Chromosomal aberrations occur with great frequency and some specificity in leukemia and other hematologic malignancies. The most common outcome of these rearrangements is the formation of a fusion gene, comprising portions of 2 genes normally present in the cell. These fusion proteins are presumed to be oncogenic; in many cases, animal models have proven them to be oncogenic. One of the most promiscuous fusion partner genes is the newly identified NUP98 gene, located on chromosome 11p15.5, which to date has been observed fused to 15 different fusion partners. NUP98 encodes a 98 kD protein that is an important component of the nuclear pore complex, which mediates nucleo-cytoplasmic transport of protein and RNA. The fusion partners of NUP98 form 2 distinct groups: homeobox genes and non-homeobox genes. All NUP98 fusions join the N-terminal GLFG repeats of NUP98 to the C-terminal portion of the partner gene, which, in the case of the homeobox gene partners, includes the homeodomain. Clinical findings are reviewed here, along with the findings of several in vivo and in vitro models have been employed to investigate the mechanisms by which NUP98 fusion genes contribute to the pathogenesis of leukemia.
Fabiana Ostronoff - One of the best experts on this subject based on the ideXlab platform.
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rearrangements in nucleoporin family of genes in childhood acute myeloid leukemia a report from children oncology group and nci cog target aml initiative
Blood, 2015Co-Authors: Fabiana Ostronoff, Robert B. Gerbing, Rhonda E Ries, Marco A Marra, Ma Yussanne, William Long, Stuart Zong, Karen Mungall, Andrew Andrew, Daniela S GerhardAbstract:Genetic alterations in the Nucleoporin ( NUP) family of genes are involved in myeloid leukemogenesis and are associated with poor prognosis. We previously showed that NUP98-NSD1 is prevalent in acute myeloid leukemia (AML) and is highly associated with FLT3 -ITD and dismal outcome. As genetic alterations in the NUP family are frequently cryptic by conventional karyotyping, their incidence has been underestimated. The COG/NCI TARGET AML initiative has performed comprehensive genome-wide characterization of diagnostic specimens from 200 pediatric AML cases in order to identify novel genetic lesions with prognostic and therapeutic significance. The interrogation of the whole genome and RNA sequencing data generated by this initiative identified numerous fusion transcripts involving the NUP family of genes, including NUP98-NSD1, NUP98-KDM5A, NUP98-HOXA9, NUP98-HMG3, NUP98-HOXD13, NUP98-PHF23, NUP98-BRWD3, CLINT-NUP98 and DEK-NUP214 . All computationally identified NUP fusions were verified by orthogonal methodology and high-throughput screening assay was developed for frequency determination. The verified NUP fusions were screened in children treated on COG AAML0531 and AAML03P1 to define their prevalence, clinical characteristics and association with clinical outcome. The impact of NUP fusions was initially evaluated in patients with cytogenetically normal AML (CN-AML). NUP fusions were observed in 14.5% (35 of 242) patients: NUP98-NSD1 (N=21) , DEK-NUP214 (N=3), NUP98-HMG3 (N=3) , NUP98-HOXD13 (N=2) , NUP98-PHF23 (N=2) and NUP98-KDM5A (N=4). The NUP fusions NUP98-BRWD3, NUP98-HOXA9 and CLINT-NUP98 were not found in CN-AML patients. Demographics and disease characteristics of CN-AML patients with and without NUP fusions were compared. Although patients of Asian descent comprised only 7% of the study population, they harbored significantly higher number of NUP fusions (29% vs 5%, P =0.002). Among those of Asian descent with CN-AML, 35% harbored a NUP fusion. We also noted an inverse association between NUP fusions and African-Americans where NUP fusions were not identified in any of African-American patients ( P =0.031). NUP fusions were correlated with other common mutations in AML. NPM1 ( 9% vs 28%, P =0.007) and CEBPA ( 6% vs 19%, P =0.06) were rare in patients with NUP fusions, whereas FLT3 /ITD (62% vs 34%, P =0.002) and WT1 (32% vs 8%, P NUP fusions. Patients with NUP fusions had a significantly lower complete remission (CR) rate (53% vs. 77%, P =0.004) and 5-year event free survival (EFS, 32% vs 53%, P =0.003) than those without N UP fusions. Given the high co-occurrence of NUP fusions and FLT3- ITD, we investigated the prevalence and clinical correlation of NUP fusions in all FLT3 -ITD-positive patients. The prevalence of NUP fusions in FLT3- ITD patients was 26% (43 of 164). The CR rate was lower in patients co-expressing the NUP fusion and FLT3- ITD (40% vs 71%, P FLT3- ITD alone. In addition, minimal residual disease (MRD) was more common in patients co-expressing NUP fusions and FLT3- ITD (68% vs 42%, P =0.008) than in those with FLT3- ITD alone. Finally, patients co-expressing FLT3 -ITD and NUP fusions had a 5-year EFS of 28% vs 35% ( P =0.093) for those with FLT3 -ITD only. Next, we investigated the prevalence of NUP fusions in specific cytogenetic groups and found that NUP fusions were rare in patients with core binding factor and were not observed in patients with MLL rearrangements. In this study we report on the discovery, verification and frequency validation of NUP fusions, a new class of genetic alterations in AML. We demonstrate that NUP fusionsare common in pediatric patients and patients with CN-AML harboring NUP fusions have poor outcome and are more likely to have post-induction MRD than those without thesefusions. Furthermore, there is a high co-occurrence of FLT3 -ITD and NUP fusions and patients harboring both genetic lesions have a lower CR rate and high post-induction MRD than those with FLT3 -ITD alone. NUP fusions define a new subgroup of pediatric AML patients with an overall poor prognosis. AML harboring NUP fusions likely share similar mechanisms of leukemogenesis and targeting these genetic lesions will likely improve outcome in a significant subset of pediatric AML patients. Disclosures No relevant conflicts of interest to declare.
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NUP98 nsd1 and flt3 itd coexpression is more prevalent in younger aml patients and leads to induction failure a cog and swog report
Blood, 2014Co-Authors: Robert B. Gerbing, Fabiana Ostronoff, Megan Othus, Michael R Loken, Susana C Raimondi, Betsy A Hirsch, Beverly J Lange, Stephen H Petersdorf, Jerald P RadichAbstract:NUP98/NSD1 has recently been reported in association with poor outcome in acute myeloid leukemia (AML). Previous studies also observed a high overlap between NUP98/NSD1 and FLT3/ITD, raising the question as to whether the reported poor outcome is due to NUP98/NSD1 or caused by the co-occurrence of these 2 genetic lesions. We aimed to determine the prognostic significance of NUP98/NSD1 in the context of FLT3/ITD AML. A total of 1421 patients enrolled in 5 consecutive Children's Oncology Group/Children's Cancer Group and SWOG trials were evaluated. NUP98/NSD1 was found in 15% of FLT3/ITD and 7% of cytogenetically normal (CN)-AML. Those with dual FLT3/ITD and NUP98/NSD1 (82% of NUP98/NSD1 patients) had a complete remission rate of 27% vs 69% in FLT3/ITD without NUP98/NSD1 (P < .001). The corresponding 3-year overall survival was 31% vs 48% (P = .011), respectively. In CN-AML, patients with concomitant NUP98/NSD1 and FLT3/ITD had a worse outcome than those harboring NUP98/NSD1 only. In multivariate analysis, the dual NUP98/NSD1 and FLT3/ITD remained an independent predictor of poor outcome, and NUP98/NSD1 without FLT3/ITD lost its prognostic significance. Our study demonstrates that it is the interaction between NUP98/NSD1 and FLT3/ITD that determines the poor outcome of patients with NUP98/NSD1 disease.
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co expression of NUP98 nsd1 and flt3 itd is more prevalent in younger aml patients and leads to high risk of induction failure a cog and swog report
Blood, 2014Co-Authors: Fabiana Ostronoff, Robert B. Gerbing, Megan Othus, Michael R Loken, Susana C Raimondi, Betsy A Hirsch, Beverly J Lange, Stephen H Petersdorf, Jerald P Radich, Frederick R AppelbaumAbstract:NUP98/NSD1 has recently been reported in association with poor outcome in acute myeloid leukemia (AML). Previous studies also observed a high-overlap between NUP98/NSD1 and FLT3/ITD, raising the question as to whether the reported poor outcome is due to NUP98/NSD1, or caused by the co-occurrence of these two genetic lesions. We aimed to determine the prognostic significance of NUP98/NSD1 in the context of FLT3/ITD AML. A total of 1421 patients enrolled in five consecutive COG/CCG and SWOG trials were evaluated. NUP98/NSD1 was found in 15% of FLT3/ITD and 7% of cytogenetically normal (CN-) AML. Those with dual FLT3/ITD and NUP98/NSD1 (82% of NUP98/NSD1 patients) had a complete remission (CR) rate of 27% versus 69% in FLT3/ITD without NUP98/NSD1 (P
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cryptic NUP98 nsd1 translocations are highly prevalent in flt3 itd positive acute myeloid leukemia and lead to high rate of induction failure report from children s oncology group
Blood, 2012Co-Authors: Fabiana Ostronoff, Robert B. Gerbing, Todd A. Alonzo, Michael R Loken, Susana C Raimondi, Betsy A Hirsch, Laura Pardo, Richard Aplenc, Lillian Sung, Samir B KahwashAbstract:Abstract 529 The nucleoporins (NUP) are a family of proteins, which form the building blocks of the nuclear pore complex. Translocations involving NUP family members NUP214 and NUP98 have been reported in acute myeloid leukemia (AML). DEK/NUP214 (also known as DEK/CAN, t(6;9)) is a known translocation in AML that is highly associated with FLT3/ITD and adverse outcome (see presentation by Moraleda P. et al). By Whole Transcript Sequencing (RNA Seq) we identified 2 cases of NUP98/NSD1 fusions by patients with cytogenetically normal (CN-) AML, both with FLT3/ITD. Recent studies by Hollink I. et al demonstrated high prevalence of FLT3/ITD in patients with NUP98/NSD1 translocations and its association with adverse outcome. Given the significant overlap between DEK/NUP214, NUP98/NSD1 fusions and FLT3/ITD, we studied the prevalence of these fusion transcripts in patients with FLT3/ITD to define the prognostic significance of genomic alteration and their contribution to clinical outcome. Pretreatment samples from patients with FLT3/ITD (N=117) as well as those with CN-AML (N=166) treated on COG-AAML0531 underwent evaluation for NUP98/NSD1 fusion transcripts RT-PCR. Fusion transcripts, as well as the break point junction was verified by Sanger sequencing. Presence of NUP98/NSD1 transcript was correlated with disease characteristics and clinical outcome in patients with FLT3/ITD. In patients with FLT3/ITD (N=117) NUP98-NSD1 was detected in 15 patients (13%). Demographics and disease characteristics of FLT3/ITD patients were compared between those with and without NUP98/NSD1. There were no significant differences in the median age (11 vs. 13 years, p=0.19) or blast % (85% vs. 80%, p=0.23) at diagnosis between patients with and without NUP98/NSD1. Mutations in NPM1 and CEBPA were not detected in those with dual FLT3/ITD and NUP98/NSD1; however, WT1 was significantly more common in FLT3/ITD patients with NUP98/NSD1 than in those without it (43% vs. 13%, p=0.01). Complete remission (CR) rates were compared in FLT3/ITD patients with and without NUP98/NSD1. CR rate in those with and without NUP98/NSD1 was 28% vs. 73% (p=0.002). Moreover, FLT3/ITD patients harboring NUP98/NSD1 were also more likely to have post-induction minimal residual disease (MRD) than those without NUP98/NSD1 (75% vs. 40.6%, p=0.03). In addition to patients with NUP98/NSD1, eight additional patients had NUP214/CAN translocation (i.e., t(6;9)), and cumulatively, translocations involving these two NUP genes accounted for 20% of patients with FLT3/ITD. CR rates in FLT3/ITD-positive patients with and without NUP translocations was determined. Those with NUP98 or NUP214 translocations had a CR rate of 40% compared to 74% in those without NUP translocations (p= 0.001). Further, the presence and prognostic significance of NUP98/NSD1 was then evaluated in CN-AML. The prevalence NUP98/NSD1 in this patient population was 7.8%. Of note, seventy-nine percent of the CN-AML patients with NUP98/NSD1 harbored FLT3/ITD as well. The CR rate for CN-AML harboring NUP98/NSD1 was significantly lower than in those without it (50% vs. 79.5%, p=0.03). When analyzing CN-AML patients who harbored both NUP98/NSD1 and FLT3/ITD, only 33% achieved CR, whereas all patients who with NUP98/NSD1 without FLT3/ITD achieved CR. Although the CR rate does not appear to be affected, AML patients with FLT3-ITD have higher relapse rates and therefore inferior outcome. We now show that among patients with FLT3/ITD, those with concurrent NUP fusions have a very low-rate of CR and high post-induction MRD than those without this fusion. The high prevalence of FLT3/ITD among NUP patients is likely not random and it is conceivable that NUP and FLT3/ITD have cooperating functional consequences that lead to a distinct leukemic phenotype and enhanced drug resistance. In conclusion, the presence of NUP in FLT3-ITD patients identifies a distinct subgroup of patients with a very high-rate of induction failure. FLT3-ITD patients should be further categorized according to the presence of NUP to improve risk-stratification of pediatric and young adult AML patients and help clinicians to identify those at very high-risk for induction failure. New therapy strategies are needed for this subgroup of patients with highly resistant disease. Disclosures: Loken:Hematologics, Inc: Employment, Equity Ownership. Pardo:Hematologics Inc: Employment.
Iris H I M Hollink - One of the best experts on this subject based on the ideXlab platform.
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NUP98 jarid1a is a novel recurrent abnormality in pediatric acute megakaryoblastic leukemia with a distinct hox gene expression pattern
Leukemia, 2013Co-Authors: J D E De Rooij, Iris H I M Hollink, Susan T C J M Arentsenpeters, Janneke Van Galen, Edwin Sonneveld, Berna H Beverloo, A Baruchel, J Trka, D Reinhardt, M ZimmermannAbstract:Cytogenetic abnormalities and early response to treatment are the main prognostic factors in acute myeloid leukemia (AML). Recently, NUP98/NSD1 (t(5; 11)(q35; p15)), a cytogenetically cryptic fusion, was described as recurrent event in AML, characterized by dismal prognosis and HOXA/B gene overexpression. Using split-signal fluorescence in situ hybridization, other NUP98-rearranged pediatric AML cases were identified, including several acute megakaryoblastic leukemia (AMKL) cases with a cytogenetically cryptic fusion of NUP98 to JARID1A (t(11;15)(p15;q35)). In this study we screened 105 pediatric AMKL cases to analyze the frequency of NUP98/JARID1A and other recurrent genetic abnormalities. NUP98/JARID1A was identified in 11/105 patients (10.5%). Other abnormalities consisted of RBM15/MKL1 (n=16), CBFA2T3/GLIS2 (n=13) and MLL-rearrangements (n=13). Comparing NUP98/JARID1A-positive patients with other pediatric AMKL patients, no significant differences in sex, age and white blood cell count were found. NUP98/JARID1A was not an independent prognostic factor for 5-year overall (probability of overall survival (pOS)) or event-free survival (probability of event-free survival (pEFS)), although the 5-year pOS for the entire AMKL cohort was poor (42±6%). Cases with RBM15/MLK1 fared significantly better in terms of pOS and pEFS, although this was not independent from other risk factors in multivariate analysis. NUP98/JARID1A cases were characterized by HOXA/B gene overexpression, which is a potential druggable pathway. In conclusion, NUP98/JARID1A is a novel recurrent genetic abnormality in pediatric AMKL.
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NUP98 jarid1a is a new recurrent genetic abnormality in pediatric acute megakaryoblastic leukemia with a distinct hox gene expression pattern
Blood, 2012Co-Authors: J D E De Rooij, Iris H I M Hollink, Susan T C J M Arentsenpeters, Berna H Beverloo, Janneke F. Van Galen, Marry M Van Den Heuveleibrink, A Baruchel, J Trka, D Reinhardt, Edwin SonneveldAbstract:Abstract 537 Introduction: Cure rates in pediatric AML are currently in the 60–70% range despite treatment with intensive chemotherapy. To improve prognosis new treatment targets need to be identified, hence there is a need to better understand the underlying biology. It is hypothesized that AML results from at least two types of mutations which non-randomly collaborate in leukemogenesis. The type-I aberrations confer a proliferative advantage, type-II mutations lead to impairment of hematopoietic differentiation (Kelly et al , 2002). We recently described NUP98/NSD1 as recurrent event in cytogenetically normal AML (Hollink et al , 2011). Patients with NUP98/NSD1 had dismal outcome, and a stem-cell phenotype characterized by overexpression of homeobox (HOX) A and – B genes. Using split-signal FISH on 122 pediatric AML cases without driving oncogenic mutation, 26 NUP98- rearranged cases were identified, including 1 patient with acute megakaryoblastic leukemia (AMKL). We previously reported a patient with fusion of JARID1A, located on chromosome 12p13, to NUP98, located on chromosome 11p15, in a non-Down Syndrome (DS) AMKL case (Van Zutven et al , 2006). Therefore, a large series of non-DS AMKL patients was screened for NUP98/JARID1A and for other abnormalities, including the novel CBFA2T3/GLIS2 translocation (Gruber et al , ASH2011; #757). Methods: Samples from 105 pediatric non-DS AMKL cases, diagnosed between 1998 and 2011, were obtained from the DCOG, the AML-BFM SG, the Saint-Louis Hospital in Paris, and the COG. AMKL is more common in DS patients, therefore we also screened a series of DS AMKL (n=16). Centrally reviewed clinical and cell-biological data were provided by these study groups. Translocation of NUP98/JARID1A, MLL -rearrangements, RBM15/MKL1, and CBFA2T3/GLIS2 were identified using RT-PCR, as well as molecular characterization including hospots for the following mutations: FLT3, KIT, RAS, PTPN11, NPM1, WT1, and CEBPA. HOXA and – B expression levels were analyzed using gene expression profiling (Affymetrix) in 274 pediatric AML patients (Balgobind et al , 2011) including 9 AMKL patients, and validated with quantitative real-time PCR (n=37). Results: NUP98/JARID1A translocations were identified in 11 patients (11%). Four other patients had a NUP98- aberration with unknown translocation partner based on split signal FISH. We identified 16/105 patients with RBM15/MKL1 , 13/105 with CBFA2T3/GLIS2 translocation, and 13/96 harbouring an MLL -rearrangement. Hence, specific non-random abnormalities could be defined in 61% of pediatric AMKL cases. Only 3/45 cases harboured a type-I mutation, all localized in the RAS gene. Comparing NUP98/JARID1A positive cases with negative cases in pediatric AMKL, no significant differences in patient characteristics including sex, age, and white blood cell count (WBC) were found. Considering prognosis, 5-year pEFS (22±14% vs. 36±6%, p=0.50) did not differ significantly from all other AMKL patients, nor did the cumulative incidence of relapse (56±19% vs. 54±7% p=0.9). CBFA2T3/GLIS2 translocated patients also did not differ from other AMKL patients (pEFS 19±16% vs. 36±6%, p=0.63). However, 5-year pEFS for RBM15/MKL1 translocated patients was significantly better (73±13% vs. 28±6%, p=0.043), but not in multivariate analysis adjusted for age and WBC. Gene expression analysis showed significantly higher HOXA5/A9/A10 and HOXB2/B3/B4/B5/B6 expression in NUP98/JARID1A compared to other pediatric AML cases. We did not identify any NUP98/JARID1A cases in the 16 DS AMKL patients. Discussion and conclusion: NUP98/JARID1A is a recurrent cryptic translocation in approximately 11% of pediatric AMKL cases. In 61% of all AMKL cases a type-II mutation could now be identified. Similar to NUP98-NSD1 a stem-cell phenotype was detected with persistent HOXAB -gene expression. Although NUP98/JARID1A did not influence prognosis, outcome in pediatric AMKL is unsatisfactory. NUP98 is known to recruit CREBBP/p300 resulting in histone acetylation, and transcriptional activation of HOX genes (Wang et al, 2007), suggesting that histone acetyltransferase inhibitors may be active. Moreover, JARID1A is unable to demethylate H3K4me2/3, which also results in sustained up regulation of HOX genes. This may provide options for targeted therapy. Disclosures: No relevant conflicts of interest to declare.
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NUP98 nsd1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct hox gene expression pattern
Blood, 2011Co-Authors: Iris H I M Hollink, Susan T C J M Arentsenpeters, Marta Pratcorona, Jenny E Kuipers, Janneke Van Galen, Saman Abbas, Marry M Van Den Heuveleibrink, Edwin Sonneveld, Berna H Beverloo, Gertjan J. L. KaspersAbstract:Translocations involving nucleoporin 98kD ( NUP98 ) on chromosome 11p15 occur at relatively low frequency in acute myeloid leukemia (AML), but can be missed with routine karyotyping. In this study, high-resolution genome-wide copy number analyses revealed cryptic NUP98/NSD1 translocations in 3 of 92 cytogenetically-normal (CN-)AML cases. To determine their exact frequency, we screened >1000 well-characterized pediatric and adult AML cases using a NUP98/NSD1 -specific RT-PCR. Twenty-three cases harbored the NUP98/NSD1 fusion, representing 16.1% of pediatric and 2.3% of adult CN-AML patients. NUP98/NSD1 -positive AML cases had significantly higher white blood cell counts (median 147x109/l), more frequent FAB-M4/M5 morphology (in 63%), CN-AML (in 78%), FLT3 /ITD (in 91%) and WT1 mutations (in 45%) than NUP98/NSD1 -negative cases. NUP98/NSD1 was mutually exclusive with all recurrent type-II aberrations. Importantly, NUP98/NSD1 was an independent predictor for poor prognosis; 4-year event-free survival was below 10% for both pediatric and adult NUP98/NSD1 -positive AML patients. NUP98/NSD1 -positive AML showed a characteristic HOX -gene expression pattern, distinct from e.g. MLL -rearranged AML, and the fusion protein was aberrantly localized in nuclear aggregates, providing insight into the leukemogenic pathways of these AMLs. Taken together, NUP98/NSD1 identifies a previously unrecognized group of young AML patients, with distinct characteristics and dismal prognosis, for whom new treatment strategies are urgently needed.
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NUP98 nsd1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct hox gene expression pattern
Blood, 2011Co-Authors: Iris H I M Hollink, Susan T C J M Arentsenpeters, Marta Pratcorona, Jenny E Kuipers, Saman Abbas, Edwin Sonneveld, Berna H Beverloo, Janneke F. Van Galen, Marry M Van Den Heuveleibrink, Gertjan J. L. KaspersAbstract:Translocations involving nucleoporin 98kD (NUP98) on chromosome 11p15 occur at relatively low frequency in acute myeloid leukemia (AML) but can be missed with routine karyotyping. In this study, high-resolution genome-wide copy number analyses revealed cryptic NUP98/NSD1 translocations in 3 of 92 cytogenetically normal (CN)-AML cases. To determine their exact frequency, we screened > 1000 well-characterized pediatric and adult AML cases using a NUP98/NSD1-specific RT-PCR. Twenty-three cases harbored the NUP98/NSD1 fusion, representing 16.1% of pediatric and 2.3% of adult CN-AML patients. NUP98/NSD1-positive AML cases had significantly higher white blood cell counts (median, 147 × 10⁹/L), more frequent FAB-M4/M5 morphology (in 63%), and more CN-AML (in 78%), FLT3/internal tandem duplication (in 91%) and WT1 mutations (in 45%) than NUP98/NSD1-negative cases. NUP98/NSD1 was mutually exclusive with all recurrent type-II aberrations. Importantly, NUP98/NSD1 was an independent predictor for poor prognosis; 4-year event-free survival was < 10% for both pediatric and adult NUP98/NSD1-positive AML patients. NUP98/NSD1-positive AML showed a characteristic HOX-gene expression pattern, distinct from, for example, MLL-rearranged AML, and the fusion protein was aberrantly localized in nuclear aggregates, providing insight into the leukemogenic pathways of these AMLs. Taken together, NUP98/NSD1 identifies a previously unrecognized group of young AML patients, with distinct characteristics and dismal prognosis, for whom new treatment strategies are urgently needed.
Gertjan J. L. Kaspers - One of the best experts on this subject based on the ideXlab platform.
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NUP98 nsd1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct hox gene expression pattern
Blood, 2011Co-Authors: Iris H I M Hollink, Susan T C J M Arentsenpeters, Marta Pratcorona, Jenny E Kuipers, Janneke Van Galen, Saman Abbas, Marry M Van Den Heuveleibrink, Edwin Sonneveld, Berna H Beverloo, Gertjan J. L. KaspersAbstract:Translocations involving nucleoporin 98kD ( NUP98 ) on chromosome 11p15 occur at relatively low frequency in acute myeloid leukemia (AML), but can be missed with routine karyotyping. In this study, high-resolution genome-wide copy number analyses revealed cryptic NUP98/NSD1 translocations in 3 of 92 cytogenetically-normal (CN-)AML cases. To determine their exact frequency, we screened >1000 well-characterized pediatric and adult AML cases using a NUP98/NSD1 -specific RT-PCR. Twenty-three cases harbored the NUP98/NSD1 fusion, representing 16.1% of pediatric and 2.3% of adult CN-AML patients. NUP98/NSD1 -positive AML cases had significantly higher white blood cell counts (median 147x109/l), more frequent FAB-M4/M5 morphology (in 63%), CN-AML (in 78%), FLT3 /ITD (in 91%) and WT1 mutations (in 45%) than NUP98/NSD1 -negative cases. NUP98/NSD1 was mutually exclusive with all recurrent type-II aberrations. Importantly, NUP98/NSD1 was an independent predictor for poor prognosis; 4-year event-free survival was below 10% for both pediatric and adult NUP98/NSD1 -positive AML patients. NUP98/NSD1 -positive AML showed a characteristic HOX -gene expression pattern, distinct from e.g. MLL -rearranged AML, and the fusion protein was aberrantly localized in nuclear aggregates, providing insight into the leukemogenic pathways of these AMLs. Taken together, NUP98/NSD1 identifies a previously unrecognized group of young AML patients, with distinct characteristics and dismal prognosis, for whom new treatment strategies are urgently needed.
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NUP98 nsd1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct hox gene expression pattern
Blood, 2011Co-Authors: Iris H I M Hollink, Susan T C J M Arentsenpeters, Marta Pratcorona, Jenny E Kuipers, Saman Abbas, Edwin Sonneveld, Berna H Beverloo, Janneke F. Van Galen, Marry M Van Den Heuveleibrink, Gertjan J. L. KaspersAbstract:Translocations involving nucleoporin 98kD (NUP98) on chromosome 11p15 occur at relatively low frequency in acute myeloid leukemia (AML) but can be missed with routine karyotyping. In this study, high-resolution genome-wide copy number analyses revealed cryptic NUP98/NSD1 translocations in 3 of 92 cytogenetically normal (CN)-AML cases. To determine their exact frequency, we screened > 1000 well-characterized pediatric and adult AML cases using a NUP98/NSD1-specific RT-PCR. Twenty-three cases harbored the NUP98/NSD1 fusion, representing 16.1% of pediatric and 2.3% of adult CN-AML patients. NUP98/NSD1-positive AML cases had significantly higher white blood cell counts (median, 147 × 10⁹/L), more frequent FAB-M4/M5 morphology (in 63%), and more CN-AML (in 78%), FLT3/internal tandem duplication (in 91%) and WT1 mutations (in 45%) than NUP98/NSD1-negative cases. NUP98/NSD1 was mutually exclusive with all recurrent type-II aberrations. Importantly, NUP98/NSD1 was an independent predictor for poor prognosis; 4-year event-free survival was < 10% for both pediatric and adult NUP98/NSD1-positive AML patients. NUP98/NSD1-positive AML showed a characteristic HOX-gene expression pattern, distinct from, for example, MLL-rearranged AML, and the fusion protein was aberrantly localized in nuclear aggregates, providing insight into the leukemogenic pathways of these AMLs. Taken together, NUP98/NSD1 identifies a previously unrecognized group of young AML patients, with distinct characteristics and dismal prognosis, for whom new treatment strategies are urgently needed.
