Die Rolle von ASXL1 Mutationen bei der Entstehung von Myeloproliferativen Neoplasien in vivo
Zusammenfassung der Projektergebnisse
In this study, we established a Calrdel52-Asxl1mut mouse model with an exacerbation in MPN phenotype, resembling observations in human CALR mutant MPN. Our data show that mutant Asxl1 drives the development of an aberrant MF-associated megakaryocyte phenotype in Calrdel52 mice, with distinct changes in H3 epigenetic marks that alter the gene expression signature of Calrdel52-Asxl1mut megakaryocytes. Using these data, we are in the process of validating targets with the long-term goal to identify novel therapeutic targets in MPN patients harboring ASXL1 mutations. To map locus-specific histone alterations to genes of interest in MxCre-Calrdel52-Asxl1mut mice, we will next use Cleavage Under Targets & Release Using Nuclease (CUT&RUN), a novel assay to analyze native chromatin on target-specific sites to supplement the proteomic profiling data we acquired by GCP. Furthermore, we submitted bone marrow samples from MxCre-Calrdel52 and MxCre-Calrdel52-Asxl1mut mice for single cell RNAseq, to verify our ex vivo megakaryocyte data in a native setting. The final step of this study will be to transfer the generated data to a human model. We will use both bone marrow biopsies from CALR and CALR-ASXL1 mutant patients and patient-derived induced pluripotent stem (iPS) cells. iPS cells are being generated in collaboration with the Icahn School of Medicine at Mount Sinai, NY, USA. To ensure concordance with my data generated using a Calr-mutant thrombocythemia mouse model, we will utilize iPS cells from CALR-mutant ET patients to validate the mutant CALR-ASXL1 epigenetic footprint and specific identified targets in patient-derived iPS cells.
Projektbezogene Publikationen (Auswahl)
- Murine Models of Myelofibrosis. Cancers (Basel). 2020:12(9):2381
Jacquelin S, Kramer F, Mullally A and Lane SW
(Siehe online unter https://doi.org/10.3390/cancers12092381) - Mutant Asxl1 Exacerbates the MPN Phenotype of Calrdel52 Mutant Mice with Distinct Effects on Histone H3 Modifications in Megakaryocytes. American Society of Hematology (ASH) Annual Meeting and Exposition, New Orleans, USA, 2022
Kramer F, Marneth AE, Pozdnyakova O, Hem J, Papanastasiou M, Reiter A, Carr SA and Mullally A
(Siehe online unter https://doi.org/10.1182/blood-2022-167735) - Mutant Srsf2 Diminishes Jak2V617F-Induced Erythrocytosis in Mice and Is Associated with Lower Hemoglobin in Patients with Chronic Phase JAK2-Mutant MPN. American Society of Hematology (ASH) Annual Meeting and Exposition, New Orleans, USA, 2022
Marneth AE, Jutzi JS, Kim CJ, Laurore C, Tishena A, Kramer F, Rocha AV et al.
(Siehe online unter https://doi.org/10.1182/blood-2022-158823)
