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DEK-NUP214-Fusion Identified by RNA-Sequencing of an Acute Myeloid Leukemia with t(9;12)(q34;q15).

ABSTRACT: Given the diagnostic, prognostic, biologic, and even therapeutic impact of leukemia-associated translocations and fusion genes, it is important to detect cryptic genomic rearrangements that may exist in hematological malignancies.RNA-sequencing was performed on an acute myeloid leukemia case with the bone marrow karyotype 45,X,-Y,t(9;12) (q34;q15)[16].The DEK-NUP214 and PRRC2B-DEK fusion genes were found. Reverse transcriptase polymerase chain reaction together with direct sequencing verified the presence of both. Fluorescence in situ hybridization showed that the DEK-NUP214 fusion gene was located on the 6p22 band of a seemingly normal chromosome 6.RNA-sequencing proved to be a valuable tool for the detection of a fusion of genes DEK and NUP214 in a leukemia that showed cryptic cytogenetic rearrangement of chromosome band 9q34.

SUBMITTER: Panagopoulos I

PROVIDER: S-EPMC6070322 | biostudies-literature | 2017 Nov-Dec

REPOSITORIES: biostudies-literature

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<i>DEK-NUP214</i>-Fusion Identified by RNA-Sequencing of an Acute Myeloid Leukemia with t(9;12)(q34;q15).

Panagopoulos Ioannis I Gorunova Ludmila L Torkildsen Synne S Tjønnfjord Geir E GE Micci Francesca F Heim Sverre S

Cancer genomics & proteomics 20171101 6

<h4>Background/aim</h4>Given the diagnostic, prognostic, biologic, and even therapeutic impact of leukemia-associated translocations and fusion genes, it is important to detect cryptic genomic rearrangements that may exist in hematological malignancies.<h4>Case report</h4>RNA-sequencing was performed on an acute myeloid leukemia case with the bone marrow karyotype 45,X,-Y,t(9;12) (q34;q15)[16].<h4>Results</h4>The DEK-NUP214 and PRRC2B-DEK fusion genes were found. Reverse transcriptase polymerase ...[more]

PMID: 29109093

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Project description:The translocation (6;9) is associated with a specific subtype of acute myeloid leukemia (AML). Previously, it was found that breakpoints on chromosome 9 are clustered in one of the introns of a large gene named Cain (can). cDNA probes derived from the 3' part of can detect an aberrant, leukemia-specific 5.5-kb transcript in bone marrow cells from t(6;9) AML patients. cDNA cloning of this mRNA revealed that it is a fusion of sequences encoded on chromosome 6 and 3' can. A novel gene on chromosome 6 which was named dek was isolated. In dek the t(6;9) breakpoints also occur in one intron. As a result the dek-can fusion gene, present in t(6;9) AML, encodes an invariable dek-can transcript. Sequence analysis of the dek-can cDNA showed that dek and can are merged without disruption of the original open reading frames and therefore the fusion mRNA encodes a chimeric DEK-CAN protein of 165 kDa. The predicted DEK and CAN proteins have molecular masses of 43 and 220 kDa, respectively. Sequence comparison with the EMBL data base failed to show consistent homology with any known protein sequences.

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Targeted CRM1-inhibition perturbs leukemogenic NUP214 fusion proteins and exerts anti-cancer effects in leukemia cell lines with <i>NUP214</i> rearrangements.

Project description:Chromosomal translocations fusing the locus of nucleoporin NUP214 each with the proto-oncogenes SET and DEK are recurrent in, largely intractable, acute leukemias. The molecular basis underlying the pathogenesis of SET-NUP214 and DEK-NUP214 are still poorly understood, but both chimeras inhibit protein nuclear export mediated by the β-karyopherin CRM1. In this report, we show that SET-NUP214 and DEK-NUP214 both disturb the localization of proteins essential for nucleocytoplasmic transport, in particular for CRM1-mediated protein export. Endogenous and exogenous SET-NUP214 and DEK-NUP214 form nuclear bodies. These nuclear bodies disperse upon targeted inhibition of CRM1 and the two fusion proteins re-localize throughout the nucleoplasm. Moreover, SET-NUP214 and DEK-NUP214 nuclear bodies reestablish shortly after removal of CRM1 inhibitors. Likewise, cell viability, metabolism, and proliferation of leukemia cell lines harboring SET-NUP214 and DEK-NUP214 are compromised by CRM1 inhibition, which is even sustained after clearance from CRM1 antagonists. Our results indicate CRM1 as a possible therapeutic target in NUP214-related leukemia. This is especially important, since no specific or targeted treatment options for NUP214 driven leukemia are available yet.

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