Chronic myelomonocytic leukaemia (CMML) is a clonal haematological neoplasm characterised by persistent monocytosis and dysplasia in at least one myeloid lineage. It can be subclassified into CMML-1 and CMML-2, usually based on blast count in the peripheral blood or bone marrow, with CMML-2 being associated with a shorter overall survival. Treatment options for CMML are currently lacking, but development of better therapeutic strategies is hampered by our limited understanding of CMML biology. As a result, treatment focusses on symptom reduction for most patients, and the prognosis of this disease is poor. CMML is a genetically homogeneous disease compared to most other adult cancers. Even though the number of recurrently mutated genes in CMML is low, the disease exhibits a great degree of clinical heterogeneity. This discrepancy between genetic homogeneity and clinical heterogeneity, combined with the very high mutation frequency of genes with epigenetic roles in CMML, suggests that epigenetic dysregulation plays an important role in CMML biology. Therefore, the aim of the current study was to profile the CMML epigenome in primary patient cells as compared to healthy control cells. To identify regions of epigenetic dysregulation in CMML, a combination of epigenetic techniques was used to study the CMML epigenome on multiple levels. Haematopoietic stem and progenitor cells (HSPCs), as well as monocytes, were profiled in this way, since CMML is thought to originate in haematopoietic stem cells and monocytes are the characteristic malignant population in this disease. The study revealed epigenetic suppression of the NF-κB pathway in CMML monocytes, as well as upregulation of oxidative phosphorylation in these cells. The oxidative phosphorylation pathway represents a potential therapeutic target in CMML, since it was found that healthy monocytes exhibit very low activity of this pathway. Moreover, extensive transcriptional and epigenetic dysregulation was identified in HSPCs. In line with a previous study, transcriptional differences between CMML-1 and CMML-2 were identified. Moreover, these populations were found to be epigenetically distinct as well. The current study identified extensive dysregulation of the TGF-β pathway in HSPCs, and identified the potential novel therapeutic targets MAMDC2 and KCNJ2/Kir2.1 as being epigenetically and transcriptionally dysregulated in CMML HSPCs.
A multiomic study of epigenetic dysregulation in chronic myelomonocytic leukaemia
Bossenbroek, H. (Author). 1 Aug 2023
Student thesis: Phd