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

Autor:	Cardin S; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montréal, QC, Canada., Bilodeau M; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montréal, QC, Canada., Roussy M; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montréal, QC, Canada.; Department of Biomedical Sciences.; Faculty of Medicine., Aubert L; Cell Signaling and Proteomics Research Unit, and.; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada., Milan T; Laboratory for High-Throughput Biology, Institute for Research in Immunology and Cancer, Montréal, QC, Canada., Jouan L; Integrated Centre for Pediatric Clinical Genomics, CHU Sainte-Justine Research Center, Montréal, QC, Canada., Rouette A; Integrated Centre for Pediatric Clinical Genomics, CHU Sainte-Justine Research Center, Montréal, QC, Canada., Laramée L; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montréal, QC, Canada., Gendron P; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.; Bioinformatics Platform, Université de Montréal, Montréal, QC, Canada., Duchaine J; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada., Decaluwe H; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montréal, QC, Canada.; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada., Spinella JF; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montréal, QC, Canada.; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada., Mourad S; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montréal, QC, Canada., Couture F; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montréal, QC, Canada., Sinnett D; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montréal, QC, Canada.; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada., Haddad É; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montréal, QC, Canada.; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.; Department of Microbiology, Infectiology and Immunology, CHU Sainte-Justine, Montréal, QC, Canada., Landry JR; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montréal, QC, Canada.; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.; Streamline Genomics, Montréal, QC, Canada., Ma J; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN., Humphries RK; British Columbia Cancer Agency, Vancouver, BC, Canada., Roux PP; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.; Laboratory for High-Throughput Biology, Institute for Research in Immunology and Cancer, Montréal, QC, Canada.; Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada., Hébert J; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.; Division of Hematology, and.; Québec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada; and., Gruber TA; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN., Wilhelm BT; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.; Laboratory for High-Throughput Biology, Institute for Research in Immunology and Cancer, Montréal, QC, Canada., Cellot S; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montréal, QC, Canada.; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.; Québec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada; and.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2019 Nov 12; Vol. 3 (21), pp. 3307-3321.
DOI:	10.1182/bloodadvances.2019030981
Abstrakt:	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. (© 2019 by The American Society of Hematology.)
Databáze:	MEDLINE
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