P445: CRYPTIC TRANSLOCATION T(5;11)(Q35;P15) RESULTING IN NUP98::NSD1 GENE FUSION IN ADULTS WITH DE NOVO ACUTE MYELOID LEUKEMIA (AML)

Abstract

Background: The NUP98::NSD1 fusion, a product of the cryptic translocation t(5;11)(q35;p15.5), is a recurrent genetic change in cytogenetically normal patients with AML. It occurs most frequently in children (16%) and young (2%) AML patients, very rarely in adult patients. The coexistence of internal tandem duplication of FLT3 gene (FLT3::ITD) found in more than 70% of NUP98::NSD1 positive patients is always associated with a poor prognosis and results in high frequency of induction failure. Aims: The aim of this study was to determine the incidence of the NUP98::NSD1 fusion gene in adults with AML and NUP98 rearrangement. Methods: We examined the bone marrow cells of 268 newly diagnosed AML patients using conventional karyotyping in combination with FISH (Abbott, MetaSystems) and mFISH/mBAND (MetaSystems). We used RT-PCR followed by direct sequencing to detect fusion genes. We processed the PCR product by ExoSAP-IT and directly sequenced on ABI Prism 310 genetic analyzer using the Big Dye Terminator kit v. 3.1. Results: In nine out of 268 cases we identified rearrangement of the 11p13-15 region. We confirmed t(5;11)(q35;p15.5) with NUP98::NSD1 gene fusion in four of them (4/268; 1.5%). Sequence analyses proved the NUP98-NSD1 transcript, arising from fusion of NUP98 exon 12 with exon 6 in NSD1 gene, in all four patients (2M/2F; FAB M4/M5b; age 42, 54, 64 and 64 years). FLT3::ITD mutation was detected in all of them. Specific primers and a probe have been designed to monitor minimal residual disease during therapeutic treatment of the patients. Out of 4 patients, two died (median OS 9 months) and two patients are alive (4 and 1 year after allogenic bone marrow transplantation). Summary/Conclusion: Our study demonstrated the occurrence of t(5;11)(q35;p15.5) with NUP98::NSD1 gene fusion also in adults over 60 years of age. We confirmed the NUP98::NSD1 fusion gene in 1.5% adults AML patients. With respect to the poor prognosis of the patients with NUP98::NSD1 fusion gene, we suggest pre-screening of NUP98 gene rearrangement using FISH in cytogenetically normal AML patients with confirmed FLT3::ITD mutation. Supported by MH CZ-DRO-VFN64165, DRO-UHKT00023736.