Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Episomes with the NUP214-ABL1 fusion gene have been observed in 6% of T-ALL. In this multicentric study we collected 27 cases of NUP214-ABL1-positive T-ALL. Median age was 15 years with male predominance. Outcome was poor in 12 patients. An associated abnormality involving TLX1 or TLX3 was found in all investigated cases. Fluorescent in situ hybridization revealed a heterogeneous pattern of NUP214-ABL1 amplification. Multiple episomes carrying the fusion were detected in 24 patients. Episomes were observed in a significant number of nuclei in 18 cases, but in only 1-5% of nuclei in 6. In addition, intrachromosomal amplification (small hsr) was identified either as the only change or in association with episomes in four cases and two T-ALL cell lines (PEER and ALL-SIL). One case showed insertion of apparently non-amplified NUP214-ABL1 sequences at 14q12. The amplified sequences were analyzed using array-based CGH.These findings confirm that the NUP214-ABL1 gene requires amplification for oncogenicity; it is part of a multistep process of leukemogenesis; and it can be a late event present only in subpopulations. Data also provide in vivo evidence for a model of episome formation, amplification and optional reintegration into the genome. Implications for the use of kinase inhibitors are discussed.
Leukemia 2009 Jan
PMID:Heterogeneous patterns of amplification of the NUP214-ABL1 fusion gene in T-cell acute lymphoblastic leukemia. 1892 37

Gambogic acid, the main active compound of gamboge resin of Garcinia hanburryi, has recently exhibited marked antitumour potency on solid tumours of various derivations. We demonstrate here that gambogic acid also present powerful antileukaemic potency through both growth arrest and apoptosis induction in Jurkat cells, which was accompanied by typical apoptotic morphological changes and sharp decreased expression of Bcl-xL and Bcl-2. Furthermore, nucleophosmin, recently demonstrated to be mutated and aberrantly localized in the cytoplasm of leukaemia blasts in a high proportion of patients with acute myeloid leukaemia, was over-expressed in Jurkat cells. As the sole site of nucleocytoplasmic communication, the protein components of nuclear pore complex, such as NUP98, NUP88, NUP214 complex, were also deregulated in Jurkat cells. Especially, NUP98 was found to distribute mainly at the cell membrane, while NUP88 and NUP214 situated not just at the nuclear envelope, but also in the cytoplasm. However, in vitro treatment with gambogic acid resulted in significantly reduced expression of nucleophosmin and all three nucleoporins in a dose-dependent manner. Moreover, most of NUP88 and NUP214 nucleoporins were relocated to the nuclear rim in the gambogic acid-treated cells. These results suggest that the fact that nucleophosmin and some nucleoporins might act as new targets of gambogic acid, correlates well with the sensitivity to gambogic acid, as well as the rate of apoptosis induced by gambogic acid. Mechanisms that regulate nucleocytoplasmic transport of proteins may provide novel opportunities for drug development.
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PMID:Involvement of regulations of nucleophosmin and nucleoporins in gambogic acid-induced apoptosis in Jurkat cells. 1906 80

Myeloid leukemia in this series corresponds to the myeloid neoplasms of the 4th WHO classification of pathology and genetics of tumor of haematopoietic and lymphoid tissue. The myeloid neoplasms are composed of six categories, which are 1) myeloproliferative neoplasms (MPN), a new category of 2) myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1, 3) myelodysplastic syndrome (MDS)/MPN, 4) MDS, 5) acute myeloid leukemia (AML) and related precursor neoplasms, and 6) acute leukemias of ambiguous lineage. In MPNs without chronic myelogenous leukemia, the genetic marker of JAK2 V617F is added to the diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. MDS has the new subtype of refractory cytopenia with unilineage dysplasia composed of refractory anemia, refractory neutropenia and refractory thrombocytopenia. AML with t(9; 11) (p22;q23); MLLT3-MLL, AML with t(6;9) (p23; q34); DEK-NUP214, AML with inv(3) (q21q26.2) or t(3; 3) (q21 ; q26.2); RPN1-EVI1 and AML (megakaryoblastic) with t(1; 22) (p13; q13); RBM15-MKL1 are added to the subtype of AML with recurrent genetic abnormalities, and AML with gene mutations of NPM1 and CEBPA are also added as provisional entities of it. The myeloid neoplasms of the 4th WHO classification are comprehensive and seem to be dynamic by incorporating the results of leukemia researches.
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PMID:[Classification of myeloid leukemias]. 1986 Jan 79

NUP98 is a nucleoporin that plays complex roles in the nucleocytoplasmic trafficking of macromolecules. Rearrangements of the NUP98 gene in human leukemia result in the expression of numerous fusion oncoproteins whose effect on nucleocytoplasmic trafficking is poorly understood. The present study was undertaken to determine the effects of leukemogenic NUP98 fusion proteins on CRM1-mediated nuclear export. NUP98-HOXA9, a prototypic NUP98 fusion, inhibited the nuclear export of two known CRM1 substrates: mutated cytoplasmic nucleophosmin and HIV-1 Rev. In vitro binding assays revealed that NUP98-HOXA9 binds CRM1 through the FG repeat motif in a Ran-GTP-dependent manner similar to but stronger than the interaction between CRM1 and its export substrates. Two NUP98 fusions, NUP98-HOXA9 and NUP98-DDX10, whose fusion partners are structurally and functionally unrelated, interacted with endogenous CRM1 in myeloid cells as shown by co-immunoprecipitation. These leukemogenic NUP98 fusion proteins interacted with CRM1, Ran, and the nucleoporin NUP214 in a manner fundamentally different from that of wild-type NUP98. NUP98-HOXA9 and NUP98-DDX10 formed characteristic aggregates within the nuclei of a myeloid cell line and primary human CD34+ cells and caused aberrant localization of CRM1 to these aggregates. These NUP98 fusions caused nuclear accumulation of two transcription factors, NFAT and NFkappaB, that are regulated by CRM1-mediated export. The nuclear entrapment of NFAT and NFkappaB correlated with enhanced transcription from promoters responsive to these transcription factors. Taken together, the results suggest a new mechanism by which NUP98 fusions dysregulate transcription and cause leukemia, namely, inhibition of CRM1-mediated nuclear export with aberrant nuclear retention of transcriptional regulators.
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PMID:Inhibition of CRM1-mediated nuclear export of transcription factors by leukemogenic NUP98 fusion proteins. 2023 15

Research conducted in my group in the period 2006-2009 has led to a better understanding of the oncogenic mechanisms of the FIP1L1-PDGFRA and NUP214-ABL1 oncogenes. Insights into these mechanisms may help us to design novel strategies to treat leukemia. In addition, we have identified the small molecule inhibitor sorafenib as a potent inhibitor of the FIP1L1-PDGFRA and its T674I imatinib resistant mutant. Sorafenib was originally developed as a BRAF inhibitor, but our work demonstrates that sorafenib can also be used to treat FIP1L1-PDGFRA positive leukemia, demonstrating that new therapies to treat rare leukemias may be simply found by testing drugs that are already in use for the treatment of other diseases. Finally, using genome-wide screening approaches, we have identified the MYB gene as a novel oncogene implicated in the pathogenesis of T-ALL, and we suggest that MYB may represent a novel target for therapy in T-ALL as well as in other cancers.
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PMID:Identification and characterization of novel oncogenes in chronic eosinophilic leukemia and T-cell acute lymphoblastic leukemia. 2072 40

The purpose of this study was to analyze the gene rearrangement pattern of immunoglobulin and T-cell receptor (Ig/TR) and its clinical characteristics in three children with SET-NUP214 fusion gene positive leukemia/lymphoma. The transcript of SET-NUP214 fusion gene was detected by RT-nested PCR. The pattern of Ig/TR gene rearrangement was analyzed by using the BIOMED-2 multiplex PCR assays. Allelic-specific primers were designed for further monitoring the minimal residual disease (MRD). The results indicated that the fusion site located between exon 7 of SET and exon 18 of NUP214 at mRNA level in the three patients. The diagnoses were made as the mixed phenotype of acute leukemia (MPAL) for patients 1, acute T-lymphoblastic leukemia (T-ALL) for patients 2, and stage IV T-lymphoblastic lymphoma (T-LBL) for patients 3, respectively. Patient 1 responded to chemotherapy very poorly and relapsed at month 6 after hematopoietic stem cell transplantation. Patient 2 had high MRD (> 10(-2)) at the end of inducing remission therapy (day 33) which implied poor outcome, and died of toxic epidermal necrolysis and sequent serious infection. Patient 3 achieved hematological complete remission (CR) and MRD negative at day 15 and day 33 respectively. The duration of CR lasted for 30 months. Clonal TR gene rearrangements were detected in all the three patients. The rearrangements of TRD, TRG and TRB were found in patient 1 and 3. The rearrangements of TRD, TRB, IgH and IgK Kde were detected in patient 2. All the 6 TRB rearrangements detected were incomplete rearrangements, whereas 85.7% and 14.3% of the TRD, and TRG rearrangements were complete and incomplete, respectively. It is concluded that the transformation of SET-NUP214(+) leukemia/lymphoma cells may occur after the rearrangements of TRD and TRG and shortly after TRB rearrangement. The leukemia/lymphoma cells of patient 1 and 2 are more immature which may be related with poor outcome or response to chemotherapy.
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PMID:[Gene rearrangement pattern of immunoglobulin and T-cell receptor (Ig/TR) and its clinical characteristics in children with SET-NUP214 fusion gene-positive leukemia/lymphoma]. 2216 84

Hematologic malignancies are often associated with chromosomal rearrangements that lead to the expression of chimeric fusion proteins. Rearrangements of the genes encoding two nucleoporins, NUP98 and NUP214, have been implicated in the pathogenesis of several types of hematologic malignancies, particularly acute myeloid leukemia. NUP98 rearrangements result in fusion of an N-terminal portion of NUP98 to one of numerous proteins. These rearrangements often follow treatment with topoisomerase II inhibitors and tend to occur in younger patients. They have been shown to induce leukemia in mice and to enhance proliferation and disrupt differentiation in primary human hematopoietic precursors. NUP214 has only a few fusion partners. DEK-NUP214 is the most common NUP214 fusion in AML; it tends to occur in younger patients and is usually associated with FLT3 internal tandem duplications. The leukemogenic activity of NUP214 fusions is less well characterized. Normal nucleoporins, including NUP98 and NUP214, have important functions in nucleocytoplasmic transport, transcription, and mitosis. These functions and their disruptions by oncogenic nucleoporin fusions are discussed.
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PMID:Nucleoporins and nucleocytoplasmic transport in hematologic malignancies. 2465 37

Nucleoporin 214 (NUP214), previously termed CAN, is required for cell cycle and nucleocytoplasmic transport. The genetic features and clinical implications of five NUP214-associated fusion genes are described in this review. SET-NUP214 was most frequently observed in T-cell acute lymphoblastic leukemia (T-ALL), concomitant with the elevated expression of HOXA cluster genes. Furthermore, the fusion transcript may be regarded as a potential minimal residual disease marker for SET-NUP214-positive patients. Episomal amplifications of NUP214-ABL1 are specific to T-ALL patients. The NUP214-ABL1 gene is observed in ~6% of T-ALL, in children and adults. Targeted tyrosine kinase inhibitors plus standard chemotherapy appear to present a promising treatment strategy. DEK-NUP214 is formed by the fusion of exon 2 of DEK and exon 6 of NUP214. Achieving molecular negativity of DEK-NUP214 is of great importance for individual management. SQSTM1-NUP214 and NUP214-XKR3 were only identified in one T-ALL patient and one cell line, respectively. The NUP214 fusions have significant diagnostic and therapeutic implications for leukemia patients. Additional NUP214-associated fusions require identification in future studies.
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PMID:NUP214 fusion genes in acute leukemia (Review). 2512 Jun 41

The DEK oncogene is highly expressed in cells from most human tissues and overexpressed in a large and growing number of cancers. It also fuses with the NUP214 gene to form the DEK-NUP214 fusion gene in a subset of acute myeloid leukemia. Originally characterized as a member of this translocation, DEK has since been implicated in epigenetic and transcriptional regulation, but its role in these processes is still elusive and intriguingly complex. Similarly multifaceted is its contribution to cellular transformation, affecting multiple cellular processes such as self-renewal, proliferation, differentiation, senescence and apoptosis. Recently, the roles of the DEK and DEK-NUP214 proteins have been elucidated by global analysis of DNA binding and gene expression, as well as multiple functional studies. This review outlines recent advances in the understanding of the basic functions of the DEK protein and its role in leukemogenesis.
Leukemia 2015 Aug
PMID:The DEK oncoprotein and its emerging roles in gene regulation. 2576 44

Leukemias expressing constitutively activated mutants of ABL1 tyrosine kinase (BCR-ABL1, TEL-ABL1, NUP214-ABL1) usually contain at least 1 normal ABL1 allele. Because oncogenic and normal ABL1 kinases may exert opposite effects on cell behavior, we examined the role of normal ABL1 in leukemias induced by oncogenic ABL1 kinases. BCR-ABL1-Abl1(-/-) cells generated highly aggressive chronic myeloid leukemia (CML)-blast phase-like disease in mice compared with less malignant CML-chronic phase-like disease from BCR-ABL1-Abl1(+/+) cells. Additionally, loss of ABL1 stimulated proliferation and expansion of BCR-ABL1 murine leukemia stem cells, arrested myeloid differentiation, inhibited genotoxic stress-induced apoptosis, and facilitated accumulation of chromosomal aberrations. Conversely, allosteric stimulation of ABL1 kinase activity enhanced the antileukemia effect of ABL1 tyrosine kinase inhibitors (imatinib and ponatinib) in human and murine leukemias expressing BCR-ABL1, TEL-ABL1, and NUP214-ABL1. Therefore, we postulate that normal ABL1 kinase behaves like a tumor suppressor and therapeutic target in leukemias expressing oncogenic forms of the kinase.
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PMID:Normal ABL1 is a tumor suppressor and therapeutic target in human and mouse leukemias expressing oncogenic ABL1 kinases. 2686 41


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