Deciphering transcriptomic dynamics during hematopoietic malignancies: role of inflammation in bone marrow niche dysregulation

RWTH Publications (RWTH Aachen)

Abstract

Myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET),polycythemia vera (PV), and primary myelofibrosis (PMF), are characterized by abnormal blood production, constitutional symptoms, and bone marrow failure. The progression to myelofibrosis (MF) in ET and PV, or primary fibrosis in PMF, has a poor prognosis and is only reversible through allogeneic stem cell transplantation, which is viable for a limited patient subset. This thesis underscores the necessity for sustainable, non invasive diagnostic methods and novel therapeutic approaches informed by transcriptomic analysis combined with advanced bio computation alanalysis for MF. In exploring MF progression, this thesis demonstrates the potential of cell-free RNA profiling from peripheral blood to distinguish between pre-MF and advanced MF transcriptomes, offering new insights into patient stratification. This approach mirrors changes in the bone marrow niche and highlights a shift towards extra medullary hematopoies is in the spleen. The study particularly focuses on the role of the transcription factor RUNX1 in fibrosis progression and identifies Interleukin 18 (IL-18) as a key inflammatory mediator, thus uncovering novel biomarkers for MPN patient stratification. For chronic myeloid leukemia (CML), this thesis develops a high-resolution single-cell RNA sequencing atlas of CML patient bone marrow, identifying 36 cell types and revealing dynamic perturbations across various cell populations before and after tyrosine kinase inhibitor (TKI) treatment. The study finds that NF-κB pathway activation and IL-1 family cytokines are markers of inflammation and potential TKI resistance. Additionally, it uncovers an unexpected dominance of the early erythroid lineage in CML and identifies main driver genes along the differentiation trajectory, suggesting potential therapeutic targets. In investigating myelodysplastic syndrome (MDS), this thesis uses computational modeling to reveal a quiescence signature perturbation in hematopoietic stem cells in an MDS mouse model. It demonstrates the collaborative role of TP53 mutation andCsnk1a1 haploinsufficiency in the malignant transformation to acute myeloid leukemia(AML), providing important insights into disease pathogenesis. Overall, this work provides a comprehensive overview of the pathogenesis and progression of three myeloid malignancies. For MF, it proposes non invasive longitudinal monitoring via IL-18 expression in the blood. In CML, it emphasizes the stromal niche's role and identifies lineage-specific therapeutic targets. For MDS, it elucidates the mechanisms of malignant transformation, offering potential biomarkers and therapeutic targets. These findings pave the way for improved diagnosis and treatment strategies across these hematological diseases.

Authors 1

1. Mohamed Mahmoud saad Mohamed corresponding Aachen

   RWTH Aachen University

   Affiliation as printed

   RWTH