Investigating the role of cytokines in clonal hematopoiesis

Thesis

Clonal hematopoiesis of indeterminate potential (CHIP) is a hematologic disorder in which individual hematopoietic stem cells acquire a mutation which allows them to clonally expand (Genovese et al., 2014; Jaiswal et al. 2014). CHIP is known to occur disproportionately in older adults. While CHIP itself usually remains clinically benign, it has been shown that CHIP may serve as a precursor for acute myeloid leukemia (AML), a hematologic cancer which, like clonal hematopoiesis, increases in risk and mortality with age (Deschler and Lübbert, 2006). However, it is not fully known what drives CHIP mutant clones to expand, nor what causes CHIP to develop into advanced hematologic malignancies such as AML. To date, a great deal of research has focused on understanding how cell intrinsic factors, like the gene carrying the CHIP mutation and further mutations acquired during AML development, may provide insight into CHIP development and progression. However, investigating cell extrinsic factors, such as cytokine signaling, in the context of CHIP may provide additional important clues into how CHIP mutants are able to gain the clonal advantage and ultimately develop into AML. In this thesis, I undertook a large-scale panel analyzing how expression of 25 cytokines may be dysregulated in the peripheral blood of CHIP patients. I identified 5 cytokines, TNFα, IL-8, CCL7, IFNγ and FGF-basic, which had significantly dysregulated expression between CHIP patients and controls. Although these results were not significant after Bonferroni multiple testing correction, they warrant further investigation into how they may impact HSC mutant clone expansion. Additionally, I analyzed RNA-Seq data to determine how these and a few other cytokines and their receptors are differentially expressed amongst blood progenitors, both in healthy patients and AML patients. Findings from the CHIP cytokine panel and my analysis of the RNA-Seq data suggest that inflammatory signaling may play a key role in both driving HSC mutant clone expansion in CHIP and promoting the eventual development of AML.

Authors: Fabo, T

• Type of award: MSc by Research
• Level of award: Masters
• Awarding institution: University of Oxford
• Language: English
• Keywords: cytokines; clonal hematopoiesis; acute myeloid leukemia