A chromosomal rearrangement involving the nucleoporin 98 (NUP98) gene on the chromosome band 11p15 is known to be associated with myeloid malignancies with poor prognostic implications [1]. More than 30 different fusion partner genes for NUP98 are known so far [2]. Among them, the fusion with DEAD-box helicase 10 (DDX10), a putative RNA helicase gene located on chromosome 11q22, can lead to pathologic leukemogenesis and suppress the differentiation of hematopoietic progenitor cells [3]. To date, 16 cases of the NUP98-DDX10 rearrangement have been reported [4]. The majority of them were de-novo or therapy-related acute myeloid leukemia (AML) cases, with one de-novo myelodysplastic syndrome (MDS) and two therapy-related MDS cases [4]. Here, we report the first Korean case of inv(11)(p15q22)/NUP98-DDX10 in therapy-related MDS associated with ovarian cancer. The institutional review board of Samsung Medical Center, Seoul, Korea, approved this study (approval number: 2022-12-117) and waived the need for informed consent.

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A 51-year-old woman was diagnosed with epithelial ovarian cancer in 2018 and underwent mass removal surgery. After the initial surgical intervention, she received the following courses of chemotherapy and radiotherapy due to recurrent relapses of the disease: carboplatin and bevacizumab from March 2018 to July 2018, doxorubicin and carboplatin from October 2019 to April 2020, nivolumab from January 2021 to February 2021, and radiation therapy in April 2021. She was administered multiple transfusions of red blood cells and platelets along with injections of granulocyte colony-stimulating factor while receiving chemotherapy for pancytopenia. Despite the supportive care, her cytopenia persisted and could not be clinically correlated, which prompted us to perform a bone marrow (BM) investigation in May 2021. Her complete blood cell counts (CBC) on the day of the BM investigation were as follows: hemoglobin, 10.0 g/dL; white blood cells, 2.47×10⁹/L (absolute neutrophil count, 1.46×10⁹/L); platelets, 56 ×10⁹/L; and the differential count was segmented neutrophils, 59%; lymphocytes, 17%; and monocytes, 24%. The BM biopsy revealed normocellular marrow (30% cellularity), and no apparent dysplastic features in either peripheral blood cells or bone marrow precursors were observed. Chromosome analysis of BM cells showed 46,XX,inv(11)(p15q22)[14]/46,XX[5]. Fluorescent in situ hybridization analysis for MLL[t(11q23)] (Vysis LSI MLL dual color, break apart rearrangement probe) revealed no abnormal signals. Due to the insufficient BM specimens, RNA was extracted from peripheral blood leukocytes, and the NUP98-DDX10 fusion transcripts were detected via reverse transcription-PCR (RT-PCR) using previously described primers [6]. Direct sequencing revealed the junction between exon 14 of NUP98 and exon 7 of DDX10 (type II) (Fig. 1). Based on these findings, and her past treatment history for ovarian cancer, the patient was finally diagnosed with therapy-related myeloid neoplasm (t-MN). She resumed chemotherapy after receiving conservative treatment, including transfusions and eltrombopag for severe thrombocytopenia; however, her CBC was not recovered. She was lost to follow-up after her last visit, five months after the BM investigation.

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The NUP98 rearrangement is expected to be newly added as one of the defining genetic abnormalities of AML in the upcoming 5th edition of the World Health Organization Classification of Hematolymphoid Tumors, given its multiple partner genes and prognostic implications [7]. NUP98, which encodes a component of the nuclear pore complex, is known to produce aberrant proteins by fusion with various partner genes [1]. The nuclear pore complexNUP-98 provides a bidirectional route for the transportation of small to large materials, including ions, peptides, and proteins, between the nucleus and cytoplasm [1]. DDX10 encodes proteins that are involved in RNA splicing, translation initiation, and ribosome assembly [8]. In 1997, NUP98-DDX10 fusion was first described, along with its potential for inducing tumorigenesis [6]. Three types of isoforms have been identified with respect to the NUP98-DDX10 fusion [9]. Type I is the fusion of NUP98 exon 12 (NM_139131.1) with DDX10 exon 6 (NM_004398.2), and only one case has been reported [9]. Type II is the fusion of NUP98 exon 14 with DDX10 exon 7 and is the most common type. Type III is the fusion of NUP98 exon 15 (nucleotide 2023) with DDX10 exon 7 (nucleotide 914) [9]. This rare but recurrent chromosomal abnormality has been discussed for several years; however, the exact mechanism of its fusion and the role of each isoform are yet to be established [4, 9]. Nakao et al. demonstrated that the NUP98-DDX10 fusion transcript may be associated with the t-MN due to DNA-topoisomerase II inhibitors, which are used in cancer therapy [5]. The patient described in this case report received doxorubicin together with carboplatin and radiation therapy for ovarian cancer. Of note, her hematopoietic cells had no dysplastic features or increased blasts. As a result, t-MN could not be considered for differential diagnosis without detection of the inversion of chromosome 11 upon chromosome analysis and subsequent RT-PCR examination to identify the fusion. This case indicates the significance of meticulous clinical correlation and genetic investigation for the diagnosis of t-MN, which is particularly relevant in cases with cryptic rearrangements.

To our knowledge, this is the first case of t-MN with inv(11)(p15q22)/NUP98-DDX10 in Korea. Data from more cases are needed for elucidation of the clinical and therapeutic implications of inv(11)(p15q22)/NUP98-DDX10 in t-MN.

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