- Jul 05 2023
- 4:00 pm - 4:45 pm
- SCOG event
‘Recent Advances in Single Cell Omics’:
55. Mark Hartmann (DKFZ Heidelberg)
We are excited to announce the next speaker of our SCOG Virtual Lecture Series ‘Recent Advances in Single Cell Omics’: Mark Hartmann (DKFZ Heidelberg).
‘RAS-Pathway Mutations Drive Onco-Fetal Reprogramming in Juvenile Myelomonocytic Leukemia’
Tight control of fetal development ensures the faithful generation of fully functional organisms. Errors during this critical phase have been linked to pathogenesis of pediatric cancers, which are often characterized by a persistence of fetal molecular programs. In contrast, reactivation of fetal-like molecular signatures have been linked to tumorigenesis in adult cancers. Such onco-fetal reprogramming may affect various cells of the tumor microenvironment.
In the present study, we performed an in-depth multi-modal analysis of juvenile myelomonocytic leukemia (JMML) to identify molecular distinctions between low- and high-risk JMML. We hypothesized that risk groups in JMML arise from hematopoietic stem cells (HSCs), which acquire driving RAS mutations at different developmental stages. We applied single-cell RNA sequencing (scRNA-seq) and identified HSCs as leukemia propagating cells. This was confirmed by ultra-low input whole-genome bisulfite sequencing (WGBS), revealing genome-wide DNA methylation changes and hence the conservation of risk-associated reprogramming across hematopoiesis.
Systematic comparison of JMML HSCs to healthy fetal, neonatal, juvenile, and adult HSCs revealed variegated developmental transcription signatures across patients. On the contrary, JMML HSCs were epigenomically most similar to postnatal HSCs. However, high-risk HSCs showed clear fetal-like signatures imprinted in their DNA methylomes, hijacking cancer hallmarks such as inflammation, stemness, and proliferation. Using a conditional knock-in mouse expressing the most frequent driver mutation in JMML (Ptpn11-E76K), we were able to confirm that RAS hyperactivation in HSCs is sufficient to re-activate fetal-like gene expression signatures in vivo.
Finally, integrative analysis of transcriptome and methylome data identified genome-wide disease- and subgroup-specific aberrations, which were enriched for cell surface markers and represent novel prognostic biomarkers in JMML. Moreover, therapeutic targeting of CD52 efficiently depleted leukemic cells and improved survival in a patient-derived xenograft model.
In summary, integrative multi-omics analyses of JMML HSCs identified onco-fetal reprogramming as a hallmark of high-risk JMML. We demonstrated that expression of JMML driver mutations is sufficient for the induction of fetal-like molecular programs. Finally, we identified novel prognostic biomarkers and validated CD52 as a therapeutic target for high-risk JMML.
Further information on participation, the program and the application for a lecture can be found below.
VIRTUAL LECTURE SERIES: 'Recent Advances in Single Cell Omics'
- Monthly event on Wednesdays at 4 pm (CEST)
- 30 min presentation, followed by 15 min discussion / Q&A
The virtual lecture series includes biweekly presentations about current single cell research. In addition to selected presentations by invited guests, we would particularly like to offer SCOG partners a platform to present their work to the network (read below how to apply).
The program will be updated regularly (see schedule below).
The Virtual Lecture Series takes place via Zoom. Please register in order to receive information on how to join the webinar. Your personal join link will be valid for all upcoming lectures of the series.
APPLY FOR LECTURE
We would kindly like to encourage the SCOG community not only to participate as an attendee but to present their work to the community. All contributions are welcome.
If you are a SCOG partner (PI/group leader) or member (Postdoc) and would like to give a talk during the lecture series, please apply by completing the form on our website. Please note that a balanced representation of topics, institutes and gender will be ensured in the selection of applications.