Session: 631. Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Bleeding and Clotting, Translational Research, Bone Marrow Failure Syndromes, platelet disorders, Diseases, thrombocytopenias
To assess the temporal changes in these gene transcripts in platelets and the potential utility to predict fibrotic progression, we then performed longitudinal analyses in two MPN mouse models. Jak2V617F knock-in mice (n=25) with stable serially transplantable disease, which resembles PV (Mullally et al., 2010), were sacrificed at 4, 8, 12, 16 and 20 weeks post-transplant, and controls (n=5) at 20 weeks. Blood counts were performed, and spleen and sternum harvested and stained with hematoxylin and eosin, and for reticulin. By 20-weeks, the platelet and leucocyte counts and hemoglobin had increased as expected. There was splenomegaly with extramedullary hematopoiesis and a mild increase in marrow reticulin. There was no significant up-regulation of Ccnd1, H2afx or Cep55 in platelet transcripts at any timepoint compared to the control mice. This data showed stability of the mouse PV phenotype and platelet transcripts, in keeping with the chronic phase of MPN.
Mice with MPLW515L (n=8) (Pikman et al., 2006) were sacrificed at 3 and 6 weeks post-transplant, and control mice (n=4) at 6 weeks. At 3-weeks post-transplant Cep55 (131.6-fold, padj<0.001) and H2afx (1.7-fold, padj<0.01) had increased in the MPLW515L mice and there was no increase in reticulin in the bone marrow. At 6-weeks platelet and leucocyte counts had increased, there was splenomegaly with extramedullary hematopoiesis including marked megakaryocytosis and marrow reticulin. On platelet transcript analysis Cep55 (154.6-fold, padj<0.001) and H2afx (2.4-fold, padj<0.001) were significantly increased; there was no significant change for Ccnd1.
Upregulation of Cep55 and H2afx in the MPLW515L mouse occurred prior to the accumulation of bone marrow reticulin and development of MF phenotype. This suggests that up-regulation of Cep55 and H2afx in platelets may be a predictor of disease progression from ET and PV to MF. For MPN patients, a deviation from steady-state platelet transcript levels, specifically for H2AFX and CEP55, may infer a biological transition towards the fibrotic phenotype. This novel approach utilizing platelet transcript analysis may therefore have potential for serially monitoring MPN patients and the early identification of genomic changes that may herald disease transformation to MF.
Disclosures: Collinson: Imago Biosciences: Research Funding; Merck-BOD1L1 Project: Research Funding. Wilson: University of Western Australia: Current Employment. Chuah: AbbVie: Honoraria; Thermo Fisher Scientific: Research Funding. Grove: Abbvie: Consultancy; Astellas: Consultancy, Honoraria; Otsuka Australia: Consultancy. Sidiqi: Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Antengene: Speakers Bureau; BMS: Speakers Bureau; Gilead: Speakers Bureau. Linden: Australian Council for the Certification of the Medical Scientific Laboratory Workforce (Board of Directors): Membership on an entity's Board of Directors or advisory committees; Australian Institute of Medical and Clinical Scientists (Advisory Board): Membership on an entity's Board of Directors or advisory committees; University of Sydney: Honoraria; Australian Federal Government: Honoraria; Merck: Research Funding; MPN Research Foundation: Research Funding; Department of Health, Western Australia: Research Funding; Cancer Council of Western Australia: Research Funding; University of Western Australia: Current Employment; Business Events Perth: Honoraria; International Society for the Advancement of Cytometry: Honoraria; National Health and Medical Research Council (Advisory Board): Membership on an entity's Board of Directors or advisory committees; Cancer Council of Western Australia (Advisory Board): Membership on an entity's Board of Directors or advisory committees. Fuller: Imago/Merck: Research Funding; AbbVie: Research Funding; Cytek Biosciences: Research Funding; Millennium Science Pty Ltd: Honoraria; Patent: Patents & Royalties: Erber, Fuller, Hui. Improvements in or relating to cell analysis. AU2018051148 (Australia, 2018); US20200232019 (USA, 2020); CN111448324 (China, 2020); EP2018870567 (Europe, 2020). Erber: Cytek Biosciences: Research Funding; ThermoFisher Scientific: Research Funding; Imago Biosciences: Research Funding; AbbVie: Research Funding; Luminex Corporation: Research Funding; Patent: Patents & Royalties: Erber, Fuller, Hui. Improvements in or relating to cell analysis. AU2018051148 (Australia, 2018); US20200232019 (USA, 2020); CN111448324 (China, 2020); EP2018870567 (Europe, 2020); Scopio Labs: Other: Advisor; Sysmex Corporation: Honoraria. Hoffman: Dompe: Patents & Royalties; Summitomo: Research Funding; Curis: Research Funding; Kartos Abbvie: Research Funding; Karyopharm: Research Funding; Dexcel Pharma: Research Funding; TD2: Research Funding; Silence Therapeutics: Consultancy; Cellinkos: Consultancy; Protagonist Therapeutics: Consultancy. Crispino: SAB of Alethiomics: Other: Member; Cellarity: Consultancy. Guo: Imago Biosciences, Inc., a subsidiary of Merck & Co, Inc: Research Funding; AbbVie: Research Funding; ThermoFisher Scientific: Research Funding.