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Acute Myeloid Leukemia With NUP98::NSD1 Fusion

Ke Xu,1,2* and Elisabeth Nacheva2,3

1Department of Haematology; 2Specialist Integrated Haematology Malignancy Diagnostic Service, Health Services Laboratories, University College London Hospitals NHS Foundation Trust, University College London, London, UK; 3UCL School of Life and Medical Sciences, London, UK.

*Correspondence:

Ke Xu, Department of Haematology, University College London Hospitals NHS Foundation Trust, 250 Euston Road, London NW1 2PG, UK. Phone: (+44) 02034567890, Email: Ke.xu @nhs.net.

 

image showing evidence of NUP98::NSD1 Fusion
Figure 1: (a) Bone marrow aspirate showing large blasts with no Auer rods (May-Grünwald-Giemsa stain x1000 magnification). (b) FISH showing an extra copy of NUP98 gene on chromosome 5. (c) Molecular karyotyping (aCGH) revealing deletion of NSD1 gene and gain of NUP98 gene.

A 40-year-old male presented with pancytopenia. A complete blood count showed Hgb 56 g/L, WBC 2.65 x109/L, and platelet 35 x109/L with a neutrophil 0.48 x109/L. Bone marrow aspirate showed large blasts with basophilic cytoplasm and no Auer rods (Figure 1a). By flow cytometry these cells were positive for CD34, CD117, CD33, CD13, CD15, HLA-DR, cMPO and negative for CD19, CD20, CD5, CD7, CD14, cCD3, cCD79a. Targeted acute myeloid leukemia (AML) fluorescence in situ hybridization (FISH) showed gain of one extra copy of the NUP98 gene mapped at B group chromosome, likely at 5q35 region (NUP98 break apart probe (Cytocell), Figure 1b), confirmed by array comparative genomic hybridization (aCGH, Agilent 8x60K) along with concurrent NSD1 loss indicating unbalanced t(5;11)(q35;p15.5) (Figure 1c). Myeloid next-generation sequencing (NGS) (Oncomine Myeloid Assay GX v2) revealed pathogenic variant in WT1 p.Val354CysfsTer14 (VAF 60%) and NUP98::NSD1 fusion. FLT3-ITD was positive (VAF 42%) by polymerase chain reaction (PCR). The patient was diagnosed with AML with NUP98 rearrangement, specifically NUP98::NSD1. The patient was refractory to DA (daunorubicin-cytarabine)+ midostaurin, FLA-Ida (fludarabine, cytarabine, idarubicin), gilteritinib and venetoclax/azacitidine and sadly passed away.

AML with NUP98 rearrangement is associated with adverse outcomes. NUP98 fuses with over 30 partner genes [1]. NUP98::NSD1 and NUP98::KDM5A are frequently-occurring NUP98 fusions in AML. AML with NUP98::NSD1 fusion is more frequently associated with myelomonocytic or monocytic/monoblastic morphology, FLT3-ITD and WT1 mutations. NUP98::NSD1 was an independent predictor for poor prognosis [2].

Acknowledgments

The authors received no financial support for the research, authorship, and publication of this article. The authors have no conflict of interest.

References

  1. Michmerhuizen NL, Klco JM, Mullighan CG. Mechanistic insights and potential therapeutic approaches for NUP98-rearranged hematologic malignancies. Blood. 2020; 136(20): 2275-2289.
  2. Hollink I, van den Heuvel-Eibrink MM, Arentsen-Peters STCJM, et al. NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern. Blood. 2011; 118(13): 3645-3656.