Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities

Blood Adv. 2019 Nov 12;3(21):3307-3321. doi: 10.1182/bloodadvances.2019030981.


Acute megakaryoblastic leukemia (AMKL) represents ∼10% of pediatric acute myeloid leukemia cases and typically affects young children (<3 years of age). It remains plagued with extremely poor treatment outcomes (<40% cure rates), mostly due to primary chemotherapy refractory disease and/or early relapse. Recurrent and mutually exclusive chimeric fusion oncogenes have been detected in 60% to 70% of cases and include nucleoporin 98 (NUP98) gene rearrangements, most commonly NUP98-KDM5A. Human models of NUP98-KDM5A-driven AMKL capable of faithfully recapitulating the disease have been lacking, and patient samples are rare, further limiting biomarkers and drug discovery. To overcome these impediments, we overexpressed NUP98-KDM5A in human cord blood hematopoietic stem and progenitor cells using a lentiviral-based approach to create physiopathologically relevant disease models. The NUP98-KDM5A fusion oncogene was a potent inducer of maturation arrest, sustaining long-term proliferative and progenitor capacities of engineered cells in optimized culture conditions. Adoptive transfer of NUP98-KDM5A-transformed cells into immunodeficient mice led to multiple subtypes of leukemia, including AMKL, that phenocopy human disease phenotypically and molecularly. The integrative molecular characterization of synthetic and patient NUP98-KDM5A AMKL samples revealed SELP, MPIG6B, and NEO1 as distinctive and novel disease biomarkers. Transcriptomic and proteomic analyses pointed to upregulation of the JAK-STAT signaling pathway in the model AMKL. Both synthetic models and patient-derived xenografts of NUP98-rearranged AMKL showed in vitro therapeutic vulnerability to ruxolitinib, a clinically approved JAK2 inhibitor. Overall, synthetic human AMKL models contribute to defining functional dependencies of rare genotypes of high-fatality pediatric leukemia, which lack effective and rationally designed treatments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Computational Biology / methods
  • Disease Models, Animal*
  • Disease Susceptibility
  • Gene Expression
  • Gene Expression Profiling
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunophenotyping
  • Leukemia, Megakaryoblastic, Acute / etiology*
  • Leukemia, Megakaryoblastic, Acute / pathology*
  • Leukemia, Megakaryoblastic, Acute / therapy
  • Mice
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Nuclear Pore Complex Proteins / genetics*
  • Nuclear Pore Complex Proteins / metabolism
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Retinoblastoma-Binding Protein 2 / genetics*
  • Retinoblastoma-Binding Protein 2 / metabolism
  • Xenograft Model Antitumor Assays


  • Biomarkers
  • Biomarkers, Tumor
  • Nuclear Pore Complex Proteins
  • Nup98 protein, human
  • Oncogene Proteins, Fusion
  • KDM5A protein, human
  • Retinoblastoma-Binding Protein 2