Details

Autor(en) / Beteiligte

• Cardin, Sophie
• Bilodeau, Mélanie
• Roussy, Mathieu
• Aubert, Léo
• Milan, Thomas
• Jouan, Loubna
• Rouette, Alexandre
• Laramée, Louise
• Gendron, Patrick
• Duchaine, Jean
• Decaluwe, Hélène
• Spinella, Jean-François
• Mourad, Stéphanie
• Couture, Françoise
• Sinnett, Daniel
• Haddad, Élie
• Landry, Josette-Renée
• Ma, Jing
• Humphries, R. Keith
• Roux, Philippe P.
• Hébert, Josée
• Gruber, Tanja A.
• Wilhelm, Brian T.
• Cellot, Sonia

Titel

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

Ist Teil von

• Blood advances, 2019-11, Vol.3 (21), p.3307-3321

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. •Engineered human models of high-fatality pediatric leukemia are relevant to uncover disease biomarkers and therapeutic vulnerabilities.•NUP98-KDM5A–associated AMKL expresses SELP, MPIG6B, and NEO1 biomarkers and is sensitive to pharmacologic inhibition with ruxolitinib. [Display omitted]