The cryptic translocation t(5;11)(q35;p15.5), which creates a NSD1-NUP98 fusion gene, has been associated with a deletion of the long arm of chromosome 5, del(5q), in pediatric acute myeloid leukemia (AML) patients with differentiated phenotype.
NSD1 is mutated in carcinoma of the upper aerodigestive tract (www.sanger.ac.uk/genetics/CGP/cosmic/) and also fuses to NUP98 in acute myeloid leukemia.
Our data suggest that dasatinib-navitoclax combination may offer a clinically relevant treatment strategy for AML with NUP98-NSD1 and concomitant FLT3-ITD.
We demonstrate that NUP98-NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes.
Furthermore, another type of NUP98-NSD1 fusion transcript was identified by additional RT-PCR analyses using other primers in a NUP98-NSD1-like patient, revealing the significance of this signature to detect NUP98-NSD1 gene fusions and to identify a new poor prognostic subgroup in AML.
We demonstrate that NUP98-NSD1 induces AML in vivo, sustains self-renewal of myeloid stem cells in vitro, and enforces expression of the HoxA7, HoxA9, HoxA10 and Meis1 proto-oncogenes.
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.
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.
The cytogenetically cryptic t(5;11)(q35;p15) leading to the NUP98-NSD1 fusion is a rare but recurrent gene rearrangement recently reported to identify a group of young AML patients with poor prognosis.
High PRDM16 expression identifies a prognostic subgroup of pediatric acute myeloid leukaemia correlated to FLT3-ITD, KMT2A-PTD, and NUP98-NSD1: the results of the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 trial.
High PRDM16 (also known as MEL1) expression is a representative marker of acute myeloid leukemia (AML) with NUP98-NSD1 and is a significant predictive marker for poor prognosis in pediatric AML.
Breakpoint mapping by FISH and reverse transcriptase polymerase chain reaction (RT-PCR) analysis confirmed that this was the same t(5;11) as previously identified in 3 children with AML, associated with del(5q) and resulting in the NUP98-NSD1 gene fusion.
Haploinsufficiency of the NSD1 gene is a hallmark of Sotos syndrome, and rearrangements of this gene by translocation can cause acute myeloid leukemia.
In a newly diagnosed patient with AML, conventional karyotyping showed translocation t(10;12)(q22;p13) but RNA NGS detected NUP98-NSD1 fusion transcripts from a known cryptic translocation t(5;11)(q35;p15).